Patil Dipmala, Dhaneshwar Suneela, Kadam Parag
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy, Pune-411038, Maharashtra, India.
Inflamm Allergy Drug Targets. 2015;13(6):393-405. doi: 10.2174/1871528114666150212125600.
We have reported the synthesis, characterization, in vitro release profile and preliminary pharmacological investigations of an antioxidant mutual prodrug of diacerein with thymol in our earlier communication. The present work reports the results of in vivo release studies and extensive pharmacological evaluation of this prodrug in collagenase- induced osteoarthritis and monosodium iodoacetate- induced hyperalgesia in Wistar rats. In vivo release was thoroughly studied in Wistar rats upon oral administration of the prodrug. In rat blood, release of 92.7% of diacerein and 20.5% of thymol was observed. From these studies we hypothesized that activation of prodrug could be mediated by physiological pH of blood (7.4) and serum esterases. Pharmacological screening of prodrug in collagenase and monoiodoacetate-induced osteoarthritis at a dose of 6.8 mg/kg, (BID) exhibited significant reduction in knee diameter (p<0.001), increase in paw withdrawal latency (p<0.001), and locomotor activity (p<0.001) with significantly higher anti-inflammatory and anti-osteoarthritic activities as compared to parent drug. The biochemical studies indicated a significant step-up in glucosaminoglycan level (p<0.001) and reduction in the C-reactive protein (p<0.001) and sulfated alkaline phosphatase levels (p<0.001). The histopathological and radiological studies confirmed the additive anti-osteoarthritic effect of prodrug as compared to plain diacerein. Antioxidant potential of prodrug was significantly more (p<0.001) while ulcer index was significantly lower (p<0.01) than diacerein. Interestingly, the diarrhea observed in diacerein- treated animals was not evident in animalstreated with prodrug, thymol and their physical mixture. Our findings indicate promising potential of this antioxidant prodrug to be used for long-term and safer management of OA.
我们在早期的交流中报道了双醋瑞因与百里酚的抗氧化相互前药的合成、表征、体外释放曲线和初步药理学研究。本研究报告了该前药在Wistar大鼠胶原酶诱导的骨关节炎和碘乙酸钠诱导的痛觉过敏中的体内释放研究结果和广泛的药理学评价。口服给药后，在Wistar大鼠中对前药的体内释放进行了深入研究。在大鼠血液中，观察到双醋瑞因释放了92.7%，百里酚释放了20.5%。从这些研究中我们推测，前药的活化可能由血液的生理pH值（7.4）和血清酯酶介导。前药在胶原酶和碘乙酸钠诱导的骨关节炎中以6.8 mg/kg（每日两次）的剂量进行药理学筛选，结果显示膝关节直径显著减小（p<0.001），爪部撤离潜伏期延长（p<0.001），运动活性增加（p<0.001），与母体药物相比，抗炎和抗骨关节炎活性显著更高。生化研究表明，葡糖胺聚糖水平显著升高（p<0.001），C反应蛋白（p<0.001）和硫酸化碱性磷酸酶水平降低（p<0.001）。组织病理学和放射学研究证实，与普通双醋瑞因相比，前药具有相加的抗骨关节炎作用。前药的抗氧化潜力显著更高（p<0.001），而溃疡指数显著低于双醋瑞因（p<0.01）。有趣的是，在双醋瑞因治疗的动物中观察到的腹泻在接受前药、百里酚及其物理混合物治疗的动物中并不明显。我们的研究结果表明，这种抗氧化前药在骨关节炎的长期和安全管理方面具有广阔的应用前景。
