Glutamine Therapy for Hemolysis-Associated Pulmonary Hypertension

描述（由申请人提供）： 本申请概述了L-谷氨酰胺在SCD和塔尔患者中的II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的生物标志物将被研究。 谷氨酰胺是一种条件必需氨基酸，天然存在于膳食蛋白质中。 它也可作为膳食补充剂。 它也可以被代谢为精氨酸，一氧化氮生产的氨基酸底物，在溶血条件下变得缺乏，并在PH中发挥作用。SCD患者的红细胞内谷氨酰胺水平低与PH相关。SCD和塔尔患者的血浆和红细胞内谷氨酰胺补充剂的代谢命运尚不清楚，但将在本提案中进行研究。 药代动力学（PK）研究将在正常对照组和SCD患者以及Thai伴和不伴PH患者中使用口服L-谷氨酰胺粉末或胶囊进行。 将在8小时内确定谷氨酰胺补充对这些亚组中血浆和红细胞谷氨酰胺和精氨酸生物利用度的影响。 随后将开展一项口服谷氨酰胺治疗SCD患者和塔尔PH患者的开放标签试验。本试验的计划持续时间为3年。 预计总共将入组50例患者（干预组30例，PK组另外20例）。 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的生物标志物的影响。患者将接受为期8周的口服谷氨酰胺疗程（0.1 g/kg，每日三次）。 本试验的目的是：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对增加溶血相关PH患者红细胞谷氨酰胺生物利用度的疗效。 2)确定SCD和塔尔患者血浆和红细胞中谷氨酰胺补充剂的PK和代谢结局。3)监测与L-谷氨酰胺重复给药相关的潜在毒性。 谷氨酰胺是一种营养补充剂，毒性很低，副作用很少。 在SCD患者中使用谷氨酰胺的研究表明其耐受性良好。PH是溶血性疾病的并发症，与显著的发病率和早期死亡率相关。 需要针对这些服务不足人群的溶血的新疗法。

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.