Immunology and Immunopharmacology Laboratory, College of Pharmacy, Chungnam National University, Republic of Korea.
Natural Product Laboratory, College of Pharmacy, Chungnam National University, Republic of Korea.
Int Immunopharmacol. 2023 Apr;117:109854. doi: 10.1016/j.intimp.2023.109854. Epub 2023 Feb 20.
While inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, due to compliance, drug safety, and resistance issues, new medications to replace ICSs are in high demand. Inotodiol, a fungal triterpenoid, showed a unique immunosuppressive property with a preference for mast cells. It exerted a mast cell-stabilizing activity equally potent to dexamethasone in mouse anaphylaxis models when orally administered in a lipid-based formulation, upgrading bioavailability. However, it was four to over ten times less effective in suppressing other immune cell subsets, depending on the subsets, than dexamethasone showing invariably potent inhibition. Accordingly, inotodiol affected the membrane-proximal signaling for activating mast cell functions more profoundly than other subsets. Inotodiol also effectively prevented asthma exacerbation. Importantly, considering the no-observed-adverse-effect level of inotodiol was over 15 times higher than dexamethasone, its therapeutic index would be at least eight times better,implying that inotodiol is a viable option for replacing CSs in treating asthma.
虽然吸入性皮质类固醇（ICSs）是哮喘治疗的主要药物，但由于顺应性、药物安全性和耐药性等问题，人们迫切需要新的药物来替代 ICSs。真菌三萜类化合物伊诺特二醇具有独特的免疫抑制特性，对肥大细胞具有偏好性。当以脂质制剂口服给予时，它在小鼠过敏模型中表现出与地塞米松同等强度的肥大细胞稳定作用，从而提高了生物利用度。然而，与地塞米松始终表现出强效抑制作用不同，伊诺特二醇在抑制其他免疫细胞亚群方面的效果要低四到十倍以上，具体取决于亚群。因此，伊诺特二醇对激活肥大细胞功能的膜近端信号的影响比其他亚群更为深刻。伊诺特二醇还能有效预防哮喘恶化。重要的是，考虑到伊诺特二醇的无观察到不良效应水平是地塞米松的 15 倍以上，其治疗指数至少要好 8 倍，这意味着伊诺特二醇是替代 CS 治疗哮喘的可行选择。
