Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.
Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.
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遗传性胱硫醚β-合酶缺陷型高胱氨酸尿症中氧化应激、炎症和血管功能障碍的生物标志物以及牛磺酸治疗在 1/2 期人体临床试验中的影响。
DOI：
10.1002/jimd.12085
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发表时间：
2019
影响因子：
4.2
通讯作者：
Kronqu
中科院分区：
文献类型：
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作者：
VanHove,JohanLK;Freehauf,CynthiaL;Ficicioglu,Can;Pena,LorenDM;Moreau,KerrieL;Henthorn,ThomasK;Christians,Uwe;Jiang,Hua;Cowan,TinaM;Young,SarahP;Hite,Michelle;Friederich,MarisaW;Stabler,SallyP;Spector,ElaineB;Kronqu
研究目的一项1/2期临床试验在胱硫肽β合酶（CBS）缺乏的同型半胱氨酸尿患者中进行，目的是：(a)评估牛磺酸治疗的药代动力学和安全性，(b)评估CBS缺乏的氧化应激、炎症和血管功能，(c)评估短期牛磺酸治疗的影响。方法纳入吡哆醇-无应答性CBS缺乏症患者，同型半胱氨酸bb0 ~ 50 μM，无炎症性疾病或接受抗氧化治疗。将基线时获得的氧化应激和炎症、内皮功能（肱动脉血流介导的扩张[FMD]）和疾病相关代谢物的生物标志物与正常值进行比较。在维持当前治疗的同时，患者每天两次接受75 mg/kg牛磺酸治疗，并在4小时和4天后评估治疗效果。结果14例患者（8 ~ 35岁，8男6女）入组，基线同型半胱氨酸水平为161±67 μM。研究发现，当排除先前存在的高甘油三酯血症时，高剂量牛磺酸是安全的。牛磺酸药代动力学显示，在12小时内迅速达到峰值水平，接近正常水平，但在治疗4天后积累缓慢，预给药水平升高。只有氧化应激的单一参数2,3‐dinor‐8‐异前列腺素‐F2α在基线时升高，炎症参数没有升高，总体FMD值没有变化。牛磺酸对这些参数都没有影响。然而，牛磺酸的作用与预处理FMD值密切相关；在预处理FMD值<10%的个体和与内皮功能相关的同型半胱氨酸水平>125 μM的个体中，牛磺酸显著改善了FMD。结论牛磺酸可改善CBS缺失型同型半胱氨酸尿患者的内皮功能。
Study ObjectiveA phase 1/2 clinical trial was performed in individuals with cystathionineβsynthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short‐term taurine treatment.MethodsIndividuals with pyridoxine‐nonresponsive CBS deficiency with homocysteine >50 μM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow‐mediated dilation [FMD]), and disease‐related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days.ResultsFourteen patients (8‐35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 μM. The study found high‐dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3‐dinor‐8‐isoprostaglandin‐F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 μM, pertinent to endothelial function.ConclusionTaurine improves endothelial function in CBS‐deficient homocystinuria in patients with preexisting reduced function.