Department of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy.
Department of Neuroscience, Psychology, Drug Research and Child's Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
Int J Mol Sci. 2019 Apr 18;20(8):1923. doi: 10.3390/ijms20081923.
To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg) or single i.a injection (1 mg ml, 50 µL) with NSAIDs-CAIs hybrid molecules, named and , was evaluated. The molecules and , which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, and were formulated in liposomes (lipo and lipo , both 1 mg ml) and directly administered by a single i.a. injection seven days after CFA injection. Lipo decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.
为了研究针对类风湿性关节炎相关性疼痛的新靶向分子，我们在 CFA 关节内（i.a.）注射诱导的类风湿性关节炎大鼠模型中测试了新的包含碳酸酐酶（CA）结合部分和环氧化酶抑制剂（NSAID）的双重抑制剂。进行了重复治疗和单次 i.a.注射的比较。在胫跗关节中注射 CFA（50 µL），并评估了 NSAIDs-CAIs 杂合分子（命名为 和 ）的口服重复治疗（1 mg kg）或单次 i.a.注射（1 mg ml，50 µL）的效果。 和 这两种分子在 14 天内每天给药，可显著预防 CFA 诱导的机械性伤害性（Paw 压力测试）和非伤害性刺激（von Frey 测试）、与自发性疼痛相关的姿势失衡（失能测试）和运动改变（横梁平衡测试）。此外，为了研究可能的局部活性，将 和 制成脂质体（脂质体 和 脂质体 ，均为 1 mg ml），并在 CFA 注射后 7 天通过单次 i.a.注射直接给药。脂质体 可降低对伤害性和非伤害性刺激的机械性敏感性，并改善运动协调。口服和 i.a.治疗并不能像组织学分析所示那样挽救关节。这种新型强效分子能够同时抑制碳酸酐酶和环氧化酶，在类风湿性关节炎的临床前条件下表现出高活性，强烈提示具有新的有吸引力的药效学特征。
