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.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Children's Hospital & Res Ctr at Oakland
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Morris, Claudia R; Kuypers, Frans A; Lavrisha, Lisa et al. (2013) A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98:1375-82
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