Mudgal Jayesh, Gowdra Vasantharaju S, Mudgal Piya P, Nayak Pawan G, Kumar Nitesh, Attari Zenab, Rao C Mallikarjuna, Nampurath Gopalan K
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India.
Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India.
Eur J Pharm Sci. 2016 Aug 25;91:74-83. doi: 10.1016/j.ejps.2016.06.002. Epub 2016 Jun 6.
The promising role of thiazolidin-4-ones (TZOs) against inflammatory conditions has been reported. From our lab, one of the TZO derivatives, compound 4C, exerted anti-inflammatory potential via inhibition of locally released cytokines and prostaglandin. In continuance, a detailed study was undertaken for the preclinical profiling of this promising TZO derivative against polyarthritis in rats, along with assessment of risk associated with the treatment. Male Sprague-Dawley rats were used for the adjuvant-induced arthritis (AIA) model. Based on the development of secondary lesion, the animals were randomized into different treatment groups. To establish the efficacy of the test compound, parameters such as inflammation, pain, disease progression, cytokines and prostaglandin (PG)-E2 levels and complete blood cell profile were recorded along with radiological and histological examinations of joints. The study also focused on evaluating the side effect of test compound on gastric, liver, renal, blood and cardiovascular components. Compound 4C exerted promising therapeutic effect against secondary lesions in polyarthritis in rats. It limited the progression of chronic inflammation and associated pain in rats. Modulation of cytokine signalling and arachidonate metabolism by 4C was evident from inhibition of interleukin (IL)-6, tumor necrosis factor (TNF)-α and PGE2 generation in AIA rats. Comparatively, compound 4C was safer than diclofenac to cause gastric, liver, renal, blood and cardiovascular toxicities. These finding supports the efficacy and safety profile of 4C, a TZO derivative in limiting the progression of arthritis when administered orally.
噻唑烷 - 4 - 酮（TZOs）在抗炎方面的潜在作用已有报道。我们实验室的一种TZO衍生物化合物4C，通过抑制局部释放的细胞因子和前列腺素发挥抗炎潜力。接下来，对这种有前景的TZO衍生物针对大鼠多关节炎进行了临床前详细研究，并评估了治疗相关风险。雄性Sprague-Dawley大鼠用于佐剂诱导的关节炎（AIA）模型。根据继发性病变的发展情况，将动物随机分为不同治疗组。为确定受试化合物的疗效，记录了炎症、疼痛、疾病进展、细胞因子和前列腺素（PG）-E2水平以及全血细胞谱等参数，同时对关节进行了放射学和组织学检查。该研究还着重评估受试化合物对胃、肝、肾、血液和心血管成分的副作用。化合物4C对大鼠多关节炎的继发性病变发挥了有前景的治疗作用。它限制了大鼠慢性炎症和相关疼痛的进展。从AIA大鼠中白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α和PGE2生成受到抑制可明显看出4C对细胞因子信号传导和花生四烯酸代谢的调节作用。相比之下，化合物4C在引起胃、肝、肾、血液和心血管毒性方面比双氯芬酸更安全。这些发现支持了TZO衍生物4C口服给药时在限制关节炎进展方面的疗效和安全性。
