Investigation of 4-methyl-2.2-dioxo-1h-2λ6,1-benzothiazine-3-carboxamide derivative influence on the biochemical markers of gastric mucosa in rats

Abstract

Non-steroidal anti-inflammatory drugs occupy a leading position in the pharmaceutical market, but their class-specific side effect (ulcerogenic action) significantly limits their widespread use. The N-(4-methoxybenzyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide derivative (compound NI-9) showed a pronounced analgesic effect in various models of pain syndromes. The aim of the study was to determine the effect of a new original derivative of 4-methyl-2.2-dixo-1H-2λ6,1-benzothiazine-3-carboxylic acid on the macroscopic state and biochemical parameters of the gastric mucosa of rats. The study was performed on 51 male Wistar rats. Compound NI-9 and the reference drug meloxicam were administered intragastrically once daily for 28 days at doses of 3 and 5 mg/kg, corresponding to their ED50 analgesic activity. Macroscopic indicators of GM damage, glycosaminoglycan content, phospholipid profile, level of MDA and CGP, as well as nitrates and nitrites and H2S were determined. The results were processed in the program STATISTICA 10.0 using non-parametric methods. The results showed that the carboxamide derivative was safer for the stomach because the ulcer index of compound NI-9 was 1.73 times lower than that of meloxicam. The damaging effect of the compound was more pronounced at the pre-epithelial and epithelial levels of GM protection, while the post-epithelial level (production of vasodilating molecules NO and H2S) was practically unaffected by this derivative, unlike meloxicam, which caused damage at all levels of protection. The obtained data supplement the data on the pharmacodynamics of the 4-methyl-2.2-dixo-1H-2λ6,1-benzothiazine-3-carboxylic acid derivative and determine the expediency of its further studies as a potential non-opioid analgesic.

In-depth investigation of analgesic activity of N-(4-methoxybenzyl)-4-methyl-2.2-dioxo-1H-2 λ6.1-benzothiazine-3-carboxamide derivate on different models of pain perception

“…In addition, alpha-1 and alpha-2 adrenoreceptors, dopamine receptors, and partially NMDA receptors are involved in the mechanisms of antinociceptive action of NI-9 compounds [8]. There is also a stronger effect of this compound on the system of nitrogen monoxide, as well as a stimulating effect on hydrogen sulfide metabolism, which not only promotes anti-inflammatory and analgesic activity, but also explains its greater safety against the stomach [3,9].…”

Сучасні Уявлення Про Формування Больового Синдрому Та Підходи До Його Ефективної Фармакологічної Корекції. Частина 2

“…У роботах [33,34] [36,37]. Крім того, у механізмах антиноцицептивної дії сполуки NI9 беруть участь α 1 та α 2 адренорецептори, дофамінові рецептори, а також частково -NMDA рецептори [38].…”

“…Крім того, у механізмах антиноцицептивної дії сполуки NI9 беруть участь α 1 та α 2 адренорецептори, дофамінові рецептори, а також частково -NMDA рецептори [38]. Встановлено також більш потужний вплив цієї сполуки на систему нітроген монооксиду, а також стимулюючий вплив на обмін гідроген сульфіду, що не тільки спри яє протизапальній і знеболюючій активності, але й пояснює її більшу безпеку щодо шлунка [39,40].…”