Abstract

The prolonged use of isoniazid (INH) – a highly effective drug in the treatment of tuberculosis – causes fatal liver injury. In order to overcome this adverse effect, a unique amide codrug was designed by covalently linking INH with sulfur-containing antioxidant- alpha-lipoic acid for possible hepatoprotective and antimycobacterial effect. Co-drug LI was prepared by Schotten Baumann reaction and was characterized by spectroscopic analysis. To check the bioreversibility of LI, in vitro release tests were conducted in buffers of specific pH, stomach, and intestinal homogenates of rat employing HPLC. Male Wistar rats were used for the evaluation of the hepatoprotective activity. Liver function markers, oxidative stress markers, and biochemical parameters were estimated. The antimycobacterial efficacy of LI was examined in terms of its ability to decrease the lung bacillary load in Balb/c mice infected intravenously with Mycobacterium tuberculosis. LI resisted hydrolysis in buffers of pH 1.2 (acidic), pH 7.4 (basic), and stomach homogenate of the rat while displayed significant hydrolysis (88.19%) in intestinal homogenates over a period of 6 h. The effect of LI on liver function, antioxidant and biochemical paradigms was remarkable as it reestablished the enzyme levels and restored hepatic cytoarchitecture representing its abrogating effect. The findings of antimycobacterial activity assessment evidently demonstrated that LI was as potent as INH in lowering the mycobacterial load in mice. The outcome of this exploration confirmed that the described co-drug can offer desirable safety and therapeutic benefit in the management of tuberculosis.

摘要

长期使用异烟肼（INH）——一种治疗肺结核的高效药物——会导致致命的肝损伤。为了克服这种不利影响，通过将 INH 与含硫抗氧化剂 - α-硫辛酸共价连接，设计了一种独特的酰胺联合药物，以实现可能的保肝和抗分枝杆菌作用。联合药物LI通过Schotten Baumann反应制备并通过光谱分析进行表征。为了检查 LI 的生物可逆性，在体外释放试验在特定 pH 值的缓冲液中进行，大鼠胃和肠匀浆采用 HPLC。使用雄性 Wistar 大鼠评估保肝活性。估计肝功能标志物、氧化应激标志物和生化参数。LI 的抗分枝杆菌功效根据其降低静脉内感染结核分枝杆菌的 Balb/c 小鼠的肺杆菌负荷的能力进行了检查。LI 在 pH 1.2（酸性）、pH 7.4（碱性）和大鼠胃匀浆的缓冲液中抵抗水解，而在 6 小时内在肠匀浆中表现出显着的水解（88.19%）。LI 对肝功能、抗氧化和生化模式的影响是显着的，因为它重建了酶水平并恢复了代表其消除作用的肝细胞结构。抗分枝杆菌活性评估的结果明显表明，LI 在降低小鼠分枝杆菌负荷方面与 INH 一样有效。这一探索的结果证实，所描述的联合药物可以在结核病的管理中提供理想的安全性和治疗益处。