Oral hymecromone decreases hyaluronan in human study participants.
Oral hymecromone decreases hyaluronan in human study participants.
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DOI：
10.1172/jci157983
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Bollyky, Paul L.
中科院分区：
文献类型：
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作者：
Rosser, Joelle, I;Nagy, Nadine;Goel, Riya;Kaber, Gernot;Demirdjian, Sally;Saxena, Jamie;Bollyky, Jennifer B.;Frymoyer, Adam R.;Pacheco-Navarro, Ana E.;Burgener, Elizabeth B.;Rajadas, Jayakumar;Wang, Zhe;Arbach, Olga;Dunn, Colleen E.;Kalinowski, Anissa;Milla, Carlos E.;Bollyky, Paul L.
透明质酸（HA）是一种细胞外基质糖胺聚糖，与COVID-19感染、肺动脉高压、肺纤维化和其他疾病的病理生理学有关，但不是任何获批药物的靶向药物。我们询问羟甲香豆素（4-甲基伞形酮[4-MU]），一种在欧洲批准用于胆痉挛治疗的口服药物，也可在体外和动物模型中抑制HA，是否可重新用作人类HA合成的抑制剂。我们在健康成人中进行了一项羟甲香豆素的开放标签、单中心、剂量反应研究。受试者接受羟甲香豆素，剂量为1200（n = 8）、2400（n = 9）或3600（n = 9）mg/d，每日分3次口服给药，持续4天。我们评估了羟甲香豆素的安全性和耐受性，并分析了痰液和血清中HA、4-MU和4-甲基伞形酮葡糖苷酸（4-MUG; 4-MU的主要代谢产物）的浓度。羟甲香豆素耐受性良好，剂量高达3600 mg/d。痰液和血清药物浓度均以剂量依赖性方式增加，表明剂量越高，暴露量越大。在合并的所有剂量组中，我们观察到治疗4天后痰液HA较基线显著降低。我们还观察到血清HA降低。此外，较高的基线痰液HA水平与痰液HA的较大降低相关。在暴露于口服羟甲香豆素4天后，健康人类受试者经历了痰HA水平的显著降低，表明这种口服疗法可能在其中HA与发病机制有关的肺部疾病中具有潜力。ClinicalTrials.gov NCT02780752。斯坦福大学医学催化剂、斯坦福大学SPARK、斯坦福大学创新药物加速器计划、NIH培训赠款5 T32 AI 052073 -14和T32 HL 129970。
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans. We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum. Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA. After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis. ClinicalTrials.gov NCT02780752. Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.