Russian Journal of AllergyRussian Journal of AllergyРоссийский Аллергологический Журнал1810-88302686-682XPublishing House ABV Press144510.36691/RJA1445Original study articlesОригинальные исследованияResearch ArticleAnti-inflammatory activity of the antiallergic drug 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate (theoritin)Противовоспалительная активность противоаллергического препарата 7-[4-(4-бензгидрилпиперазинил-1)бутил]-3-метилксантина сукцината (теоритин)https://orcid.org/0000-0002-4465-65091905-4758GushchinIgor S.ГущинИгорь Сергеевич
Russian Federation

MD, PhD, professor, corresponding member of Russian Academy of Sciences, head of the Departament of Clinical Immunology and Allergology

член-корреспондент РАН, доктор медицинских наук, профессор, зав. отделом клинической иммунологии и аллергологии

igushchin@yandex.ruhttps://orcid.org/0000-0003-1451-77165650-2840KryshenKirill L.КрышеньКирилл Леонидович
Russian Federation

Cand. Sci. (Biol.)

кандидат биологических наук

info@doclinika.ruhttps://orcid.org/0000-0002-8437-13133376-6819BondarenkoAndrei B.БондаренкоАндрей Борисович
Russian Federation
info@doclinika.ruNational Research Center — Institute of Immunology Federal Medical-Biological Agency of RussiaГосударственный научный центр «Институт иммунологии» Федерального медико-биологического агентстваScientific and Production Association “Home of Pharmacy”Научно-производственное объединение «Дом фармации»250520212606202118220311204202112052021Copyright ©; 2021, Pharmarus Print MediaCopyright ©; 2021, Фармарус Принт Медиа2021Pharmarus Print MediaФармарус Принт Медиаhttps://rusalljournal.ru/raj/article/view/1445

BACKGROUND: Many antagonists of histamine (H1) receptor, in addition to antihistamine action, suppress allergic inflammation by inhibiting the formation and secretion of proinflammatory cytokines. The new antiallergic drug benzhydrylpiperazinyl butylmethylxanthine succinate (theoritin), which has an antihistamine activity comparable to the known second generation H1-antihistamines, surpasses them in the ability to suppress the allergic inflammatory reaction, which allows this drug to have additional anti-inflammatory properties associated with the inhibition of the formation of proinflammatory cytokines.

AIM: This study aimed to determine the effect of theoritin on the induced release of proinflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in cell culture in comparison with the action of the inverse agonist of H1 receptor cetirizine and a known inflammation inhibitor glucocorticosteroid dexamethasone.

MATERIALS AND METHODS: U937 cells differentiated toward macrophage-like cells were used. Cytotoxicity of the substances used was assessed in the methyltetrazolium test at different incubation times (up to 24 h). Cells were stimulated with lipopolysaccharide (LPS). The tested compounds (theoritin and cetirizine) were evaluated at concentrations from 0.001 to 100 μM and dexamethasone at 10 μM was tested when added to cells 1 h before (prophylactic effect) or 1 h after (therapeutic effect) the addition of LPS. The presence of IL-6, IL-8, and TNFα in the supernatants was determined by enzyme immunoassay.

RESULTS: For cetirizine and theoritin, no cytotoxic action was found in the tested concentrations and time points. Dexamethasone inhibited the formation of IL-6 and TNFα to the initial level and IL-8 to 50%–60%. Theoritin led to a significant concentration-dependent decrease in the LPS-induced production of IL-6, IL-8, and TNFα, and at a concentration of 100 μM, the effect of theoritin was comparable with that of dexamethasone at a concentration of 10 μM. The “prophylactic” test scheme for theoritin was more effective in suppressing LPS-induced production of proinflammatory cytokines than the “curative” one. The described effect of theoritin on LPS-induced production of proinflammatory cytokines exceeded that of the reference drug cetirizine.

CONCLUSION: In addition to its antihistaminic action, theoritin, a new antiallergic agent, inhibits LPS-induced production of proinflammatory cytokines, which may be of clinical importance in suppressing allergic inflammation.

ОБОСНОВАНИЕ. Многие антагонисты Н1-рецепторов помимо противогистаминного действия подавляют аллергическое воспаление за счёт угнетения образования и секреции провоспалительных цитокинов. Новый противоаллергический препарат бензгидрилпиперазинилбутилметилксантина сукцинат (теоритин), имеющий сопоставимую с известными Н1-антигистаминными препаратами 2-го поколения противогистаминную активность, превосходит их по способности подавлять аллергическую воспалительную реакцию, что позволяет допустить наличие у этого препарата дополнительных противовоспалительных свойств, связанных с угнетением образования провоспалительных цитокинов.

ЦЕЛЬ ― определить в культуре клеток влияние теоритина на индуцированное высвобождение провоспалительных цитокинов ― интерлейкинов (ИЛ) 6, 8 и фактора некроза опухоли альфа (ФНОα) ― в сравнении с действием обратного агониста Н1-рецепторов цетиризина и известного ингибитора воспаления глюкокортикоида дексаметазона.

МАТЕРИАЛ И МЕТОДЫ. Использовали клетки U937, подвергнутые дифференцировке в сторону макрофагоподобных клеток. Цитотоксичность использованных субстанций оценивали в метилтетразолиевом тесте в разные сроки инкубации (до 24 ч). Стимуляцию клеток осуществляли липополисахаридом (ЛПС). Тестируемые соединения (теоритин и цетиризин) испытывали в концентрациях от 0,001 до 100 мкМ, дексаметазона ― 10 мкМ при добавлении к клеткам за 1 ч до (профилактическое действие) или через 1 ч после (лечебное действие) внесения ЛПС. Определение ИЛ-6, ИЛ-8 и ФНОα в надосадочных жидкостях проводили иммуноферментным методом.

РЕЗУЛЬТАТЫ. Для цетиризина и теоритина показано отсутствие цитотоксического действия в пределах испытанных концентраций и временных интервалов. Дексаметазон подавлял образование ИЛ-6 и ФНОα до исходного уровня, а ИЛ-8 ― на 50–60% в обоих режимах введения. Теоритин приводил к достоверному, зависимому от концентрации снижению ЛПС-индуцированной продукции ИЛ-6, ИЛ-8 и ФНОα, а в концентрации 100 мкМ действие теоритина было сравнимо с действием дексаметазона в концентрации 10 мкМ. Профилактическая схема испытаний теоритина была более эффективной в подавлении ЛПС-индуцированной продукции провоспалительных цитокинов, чем лечебная. Описанное действие теоритина на ЛПС-индуцированную продукцию провоспалительных цитокинов превышало таковое у препарата сравнения цетиризина.

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