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首页> 外文期刊>Drug delivery and translational research >Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study
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Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study

机译：用芳基乙酸NSAIDS的羟基氯喹双作用前药物的新药递送：设计，动力学和药理学研究

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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-1-NMR, C-13-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.
机译：类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征在于手部，脚，肘部，膝盖和颈部的受限制运动，但主要是滑膜接头。尽管病因病于恰到好处，但治疗范式正在发展，以便对症状和疾病进展进行更严格的控制。目前的趋势是在早期调节抗类风湿药物（DMARDS）的引入。羟基氯喹（HCQ）和非甾体抗炎药（NSAIDS）是两种机械主义不同的类别，广泛用于RA的管理，其中第一次在后者提供症状缓解时逮捕疾病进展。目前的工作旨在通过设计相互酯类前药来最小化非靶向部位和局部胃内胃内胃内胃内胃肠杆菌的累积问题。通过CDI偶联来实现前药的合成，通过IR，H-1-NMR，C-13-NMR，质谱和元素分析证实了结构。前药在胃的酸性环境中抵抗水解，但在小肠中表现出显着的释放。在口服对大鼠的前药物施用后，在血液中8.5-10小时中回收40.5-49％HCQ和53.4-66.8％的NSAID。尿液和粪便分别在24小时内汇集的样品分别表现出2.3-3.5％和0.75-0.9％的HCQ，没有任何完整的前药或NSAID。使用标准动物模型，前药是药理学评估的镇痛和抗炎活动。其中，具有LiCoFelone（HL）和醋Eclofenac（HA）的HCQ的前药产生优异的镇痛，改善重量增益，关节直径/爪子的标准化比HCQ和HCQ和NSAID的物理混合物。血液学和生化研究表明RBC，HB，血小板计数，总蛋白质营养素（TPN）水平的显着加入，并通过治疗方法在WBC，血清谷氨酸 - 草灭酸转氨酶（SGOT）和血清谷氨酸 - 丙酮转氨酶（SGPT）中进行下降HL和HA。通过这些新的Codrugs，在非靶向部位和NSAID的非靶向场所和局部胃内胃肠杆菌的缓慢发病和积累的问题得到了很好的解决。这些双作用相互前药的两个机械主义不同的抗关节炎药物可以进一步探索作为有效管理RA的有希望的策略。

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