safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2020-8-3-151-159safetyrisk-194Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESЭкспериментальное исследование фармакологической безопасности лекарственных средств, применяемых для купирования лихорадочного синдрома в детском возрастеSafety Pharmacology Study of Medicines Used for Febrile Syndrome Management in Childrenhttps://orcid.org/0000-0003-1451-7716КрышеньК. Л.KryshenK. L.

канд. биол. наук

ул. Заводская, д. 3, корп. 245, ГП Кузьмоловский, Всеволожский р-н, Ленинградская обл, 188663, 

Cand. Sci. (Biol.)

3/245 Zavodskaya St., Kuzmolovskiy, Vsevolozhskiy district, Leningrad region 188663

kryshen.kl@doclinika.ruhttps://orcid.org/0000-0002-7101-2469МошковА. Е.MoshkovA. E.

д-р биол. наук

ул. Малая Пироговская, д. 13/1, Москва, 119435

Dr. Sci. (Biol.)

13/1 Malaya Pirogovskaya St., Moscow 119435

moshkovster@gmail.comhttps://orcid.org/0000-0002-7164-2567ДемяновскийМ. Н.DemyanovskiyM. N.

ул. Заводская, д. 3, корп. 245, ГП Кузьмоловский, Всеволожский р-н, Ленинградская обл, 188663

3/245 Zavodskaya St., Kuzmolovskiy, Vsevolozhskiy district, Leningrad region 188663

demyanovskiy.mn@doclinika.ruhttps://orcid.org/0000-0002-0740-9357КовалеваМ. А.KovalevaM. A.

канд. биол. наук

ул. Заводская, д. 3, корп. 245, ГП Кузьмоловский, Всеволожский р-н, Ленинградская обл, 188663, 

Cand. Sci. (Biol.)

3/245 Zavodskaya St., Kuzmolovskiy, Vsevolozhskiy district, Leningrad region 188663

kovaleva.ma@doclinika.ruАкционерное общество «Научно-производственное объединение «ДОМ ФАРМАЦИИ»РоссияResearch-and-manufacturing company “Home оf Pharmacy”Russian FederationООО «ЛАБМГМУ»Россия“LABMGMU LLC”Russian Federation20201408202083151159Copyright © Крышень К.Л., Мошков А.Е., Демяновский М.Н., Ковалева М.А., 20202020Крышень К.Л., Мошков А.Е., Демяновский М.Н., Ковалева М.А.Kryshen K.L., Moshkov A.E., Demyanovskiy M.N., Kovaleva M.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/194

Изучение фармакологической безопасности лекарственных средств, применяемых в педиатрической практике, является важным этапом жизненного цикла препаратов.

Цель работы

Цель работы: изучить профиль фармакологической безопасности рекомендованного в педиатрии режима дозирования фиксированной комбинации ибупрофена и парацетамола, а также монопрепаратов ибупрофена и парацетамола при их многократном пероральном введении ювенильным крысам, и провести сравнительную оценку полученных данных.

Материалы и методы

Материалы и методы: оценку фармакологической безопасности проводили на аутбредных ювенильных крысах обоих полов. Исследовали два уровня доз каждого из препаратов — высшую терапевтическую дозу (ВТД), эквивалентную для ювенильных крыс, и дозу, превышающую эквивалентную терапевтическую дозу в три раза (3 ВТД). Животным вводили фиксированную комбинацию ибупрофена и парацетамола в форме суспензии из диспергируемых таблеток (100 мг ибупрофена + 125 мг парацетамола), ибупрофен в форме суспензии для приема внутрь, 100 мг/5 мл, и парацетамол в форме суспензии для приема внутрь, 120 мг/5 мл. Статистическую обработку проводили с помощью программного обеспечения Statistica 10.0.

Результаты

Результаты: на фоне введения ювенильным крысам ибупрофена показано увеличение концентрации мочевины крови у самок (ВТД) и у самцов (3 ВТД), у самок также было обнаружено небольшое количество лейкоцитов в моче. При введении парацетамола наблюдали увеличение содержания эритроцитов в моче у самцов крыс. Введение обоих монопрепаратов в дозе ВТД привело к снижению локомоторной активности животных. В отличие от монопрепаратов, фиксированная комбинация ибупрофена и парацетамола при введении ювенильным крысам не оказывала клинически значимого гепатотоксического и нефротоксического действия. Для всех исследуемых препаратов не было выявлено значимого влияния на сердечно-сосудистую и дыхательную системы.

Выводы

Выводы: установлен профиль фармакологической безопасности фиксированной комбинации ибупрофена и парацетамола при многократном пероральном введении ювенильным крысам, который не отличается, а в некоторых случаях является более благоприятным, чем профиль фармакологической безопасности монопрепаратов ибупрофена и парацетамола.

Summary

Summary. Safety pharmacology studies of paediatric medicines are an important stage in the life cycle of drugs.

The purpose of the study was to analyse and compare the safety pharmacology profiles of the recommended paediatric dosage regimens of a fixed ibuprofen (IBU)/paracetamol (PAR) combination and of IBU and PAR monopreparations following repeated oral administration of these products to juvenile rats.

Material and methods

Material and methods: safety pharmacology was assessed in both male and female outbred juvenile rats. Two dose levels were used in the study—the highest treatment dose (HTD) equivalent for juvenile rats, and the three-times-equivalent therapeutic dose (3 HTD). The animals were given the fixed IBU/PAR combination in the form of suspension from dispersible tablets (100 mg IBU + 120 mg PAR), IBU in the form of oral suspension (100 mg/5 mL), and PAR in the form of oral suspension (120 mg/5 mL). Statistical processing was performed using Statistica 10.0 software.

Results

Results: unlike monopreparations, the fixed IBU/PAR combination did not have clinically significant hepatotoxic or nephrotoxic effects when administered to juvenile rats. Administration of IBU alone resulted in an increase in blood urea nitrogen concentration in female rats (HTD) and male rats (3 HTD), and a small amount of leucocytes in the urine of female rats. Administration of PAR resulted in an increase in the amount of red blood cells in the urine of male rats. Administration of the monopreparations at the HTD dose led to a decrease in the locomotor activity of the animals. No significant effect on the cardiovascular or respiratory systems was observed for any of the products.

Conclusions

Conclusions: the safety pharmacology profile of the fixed IBU/PAR combination after repeated oral administration to juvenile rats did not differ much from those of IBU and PAR used alone, and in some cases was even better.

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