Glutamine Therapy for Hemolysis-Associated Pulmonary Hypertension

描述(由申请人提供)： 这项申请概述了L-谷氨酰胺在SCD和Thal患者中的2期试验。特别是这种氨基酸对精氨酸生物利用度的影响，氧化应激和溶血相关PH的生物标记物将被研究。谷氨酰胺是一种条件性必需氨基酸，天然存在于饮食蛋白质中。它也可以作为膳食补充剂。它也可以被代谢成精氨酸，精氨酸是产生一氧化氮的氨基酸底物，在溶血条件下变得缺乏，并在PH中发挥作用。SCD患者红细胞内谷氨酰胺水平低与PH有关。补充谷氨酰胺在SCD和Thal患者的血浆和红细胞内的代谢命运尚不清楚，但将在本方案中进行调查。将在正常对照组、SCD患者和泰国有或没有PH的患者中使用粉剂或胶囊形式的口服L-谷氨酰胺进行药代动力学(PK)研究。补充谷氨酰胺对血浆和红细胞中谷氨酰胺和精氨酸生物利用度的影响将在8小时内确定。随后将进行一项口服谷氨酰胺的开放标签试验，用于SCD患者和Thal PH患者。本次试验计划期限为3年。预计总共将有50名患者入选(干预组30名，PK组另外20名患者)。这项干预研究将是一项开放标签试验，以确定口服谷氨酰胺对氧化应激、精氨酸生物利用度、溶血和PH值等生物标志物的影响。患者将接受为期8周的谷氨酰胺口服(0.1g/kg，每天三次)。该试验的目的是：1)通过一项为期8周的开放标签试验，确定口服谷氨酰胺治疗在提高溶血相关性PH患者红细胞谷氨酰胺生物利用度方面的疗效。2)测定补充谷氨酰胺对SCD和Thal患者血浆和红细胞内PK和代谢的影响。3)监测反复服用L-谷氨酰胺的潜在毒性。谷氨酰胺是一种毒性很低、副作用很小的营养补充剂。在SCD患者中使用谷氨酰胺的研究表明，它的耐受性良好。PH是一种溶血性疾病的并发症，与显著的发病率和早期死亡率有关。需要针对这些服务不足的人群中的溶血的新疗法。

DESCRIPTION (provided by applicant): This application outlines a Phase 2 trial of L-glutamine in SCD and Thal patients. In particular the impact of this amino acid on arginine bioavailability, biomarkers of oxidative stress and hemolysis-associated PH will be investigated. Glutamine is a conditionally essential amino acid, naturally found in dietary protein. It is also available as a dietary supplement. It can also be metabolized to arginine, the amino acid substrate for nitric oxide production that becomes deficient in hemolytic conditions and plays a role in PH. Low levels of glutamine within the red blood cell of SCD patients are associated with PH. The metabolic fate of glutamine supplementation within plasma and erythrocytes of patients with SCD and Thal is unknown, but will be investigated in this proposal. Pharmacokinetic (PK) studies will be performed in normal controls and patients with SCD and ThaI patients with and without PH using oral L-glutamine in powder or capsule form. The impact of glutamine supplementation on plasma and erythrocyte glutamine and arginine bioavailability in these subgroups will be determined over 8 hours. An open-label trial of oral glutamine for patients with SCD and Thal patients with PH will follow. The planned duration of this trial is 3 years. It is anticipated that 50 patients will be enrolled in total (30 in the intervention arm and 20 additional patients in the PK arm). The intervention study will be an open label trial to determine the impact of oral glutamine on biomarkers of oxidative stress, arginine bioavailability, hemolysis and PH. Patients will receive an 8-week course of oral glutamine (0.1 g/kg three times daily). The objectives of the trial are: 1) To determine the efficacy of oral glutamine therapy on increasing erythrocyte glutamine bioavailability in patients with hemolysis-associated PH through an 8-week open-label trial. 2) To determine the PK and metabolic fate of glutamine supplementation within plasma and erythrocytes of patients with SCD and Thal. 3) To monitor for potential toxicities associated with repeated administration of L-glutamine. Glutamine is a nutritional supplement with very low toxicity and few side effects. Studies using glutamine in patients with SCD demonstrate that it was well tolerated. PH is a complication of hemolytic disorders that is associated with significant morbidity and early mortality. Novel therapies that target hemolysis in these underserved populations are needed.