Świerczek Artur, Pociecha Krzysztof, Plutecka Hanna, Ślusarczyk Marietta, Chłoń-Rzepa Grażyna, Wyska Elżbieta
Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, 8 Skawińska Street, 31-066 Krakow, Poland.
Pharmaceutics. 2022 May 19;14(5):1090. doi: 10.3390/pharmaceutics14051090.
Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound , being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.
自身免疫性疾病（ADs）的当前治疗策略疗效有限且会引发众多不良反应。磷酸二酯酶（PDE）4和PDE7抑制剂最近已作为多种ADs的潜在治疗方法进行了研究。在本研究中，采用了药代动力学/药效学（PK/PD）疾病进展建模方法来评估一种新型茶碱衍生物化合物（一种强效PDE4和PDE7抑制剂）的效果。研究了该化合物在体外对PDE1和PDE3的活性。利用多发性硬化症（MS）、类风湿性关节炎（RA）和自身免疫性肝炎的动物模型来评估该化合物的疗效，并在小鼠和大鼠中研究了其药代动力学。建立了一种新的化合物PK/PD疾病进展模型，该模型令人满意地预测了实验性脑脊髓炎小鼠（MS的一种动物模型）的临床评分-时间进程。化合物在所有三种ADs动物模型中均显示出高效性。同时抑制免疫细胞中的PDE类型可能构成ADs的一种替代治疗策略。本研究中提出的PK/PD脑脊髓炎和关节炎进展模型可用于未来的临床前研究，并且经过修改后，可能能够将临床前研究结果转化为临床应用。
