BACKGROUND The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.

中文翻译：

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三种 CFTR 增强剂治疗姜黄素、染料木黄酮和依伐卡托对 CFTR-S1251N 门控突变患者的临床效果

背景 天然食品补充剂姜黄素和染料木素以及药物依伐卡托被发现在携带 S1251N 门控突变的个体的类器官中作为 CFTR 增强剂是有效的，可能以协同方式。基于这些体外研究结果，我们评估了姜黄素、染料木黄酮和依伐卡托不同组合治疗的临床疗效。方法 在三项多中心试验中，携带 S1251N 突变的 CF 患者接受姜黄素+染料木黄酮、ivacaftor 和ivacaftor+染料木黄酮治疗 8 周。我们评估了肺功能、汗液氯化物浓度、CFQ-r、BMI 和粪便弹性蛋白酶的变化，以确定临床效果。我们通过评估治疗后收集的血浆浓度以及相同血浆对肠道类器官的影响来评估化合物的药代动力学特性。结果 观察到依伐卡托治疗的明确临床效果，临床参数的显着改善证明了这一点。相比之下，我们没有观察到姜黄素和/或染料木黄酮的明显临床效果，除了汗液氯化物和气道阻力小而显着的降低。食品补充剂的血浆浓度很低，类器官对这种血浆的反应也是如此。结论 我们观察到依伐卡托治疗的明确临床效果，这与肠道类器官对这种药物的高反应性一致。姜黄素和/或染料木素治疗未观察到明显的临床效果，