Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, Maharashtra, 411 038, India.
Drug Deliv Transl Res. 2017 Oct;7(5):709-730. doi: 10.1007/s13346-017-0420-5.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, H-NMR, C-NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5-49% HCQ and 53.4-66.8% of NSAIDs were recovered in 8.5-10 h in blood. Urine and feces samples pooled over a period of 24 h exhibited 2.3-3.5% and 0.75-0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是手部、脚部、肘部、膝盖和颈部关节活动受限，但主要是滑膜关节。虽然病因学尚不清楚，但治疗模式正在发展，以提供对症状和疾病进展的更严格控制。目前的趋势是在早期引入疾病修饰抗风湿药物（DMARDs）。羟氯喹（HCQ）和非甾体抗炎药（NSAIDs）是两种在 RA 管理中广泛使用的机制不同的类别，前者阻止疾病进展，而后者提供症状缓解。本工作旨在通过设计它们的互酯化前药来最小化 HCQ 在非靶向部位缓慢起始和积累以及 NSAIDs 局部胃不耐受的问题。前药的合成通过 CDI 偶联实现，结构通过 IR、H-NMR、C-NMR、质谱和元素分析确认。前药在胃的酸性环境中抵抗水解，但在小肠中表现出显著释放。将前药口服给予大鼠后，在血液中 8.5-10 h 内回收了 40.5-49%的 HCQ 和 53.4-66.8%的 NSAIDs。在 24 小时的时间段内收集的尿液和粪便样本分别显示 2.3-3.5%和 0.75-0.9%的 HCQ，而没有任何完整的前药或 NSAIDs 存在。使用标准动物模型评估前药的镇痛和抗炎活性。在所有这些研究中，与 HCQ 结合的利可福龙（HL）和醋氯芬酸（HA）的前药产生了更好的镇痛作用，增加了体重增加，使关节直径/足体积正常化，优于 HCQ 和 HCQ 与 NSAIDs 的物理混合物。血液学和生化研究表明，通过 HL 和 HA 治疗，红细胞（RBC）、血红蛋白（Hb）、血小板计数、总蛋白营养（TPN）水平显著上升，白细胞（WBC）、血清谷氨酸-草酰乙酸转氨酶（SGOT）和血清谷氨酸-丙酮酸转氨酶（SGPT）水平下降。通过这些新型共前药，HCQ 在非靶向部位缓慢起始和积累以及 NSAIDs 局部胃不耐受的问题得到了很好的解决。这两种机制不同的抗关节炎药物的双作用互前药可以进一步探索，作为有效治疗 RA 的有前途的策略。
