Oxidative stress is integral to pathophysiology of sickle cell disease and thalassemia. Precipitated globin chains in thalassemia generate free radicals, while increased superoxide, vaso-occlusive crises (VOC) and depletion of NO contribute to pro-oxidant state in SCD. To combat oxidative stress in hemoglobinopathies, potent antioxidant compounds able to neutralize free radicals in both aqueous and lipophilic environments are required. A combination of α-lipoic acid (LA) and acetyl L-carnitine (ALCAR) was given to 14 subjects (SCD = 11, HbH-Constant Spring = 3) who were not on regular red cell transfusions. All subjects except 1 with SCD completed the study. SCD subjects (SS=9, SC=1) had history of frequent VOC with 7/10 receiving hydroxyurea therapy. All subjects were at baseline clinical status with no acute complications from the disease. LA 400 mg and ALCAR 1,000 mg per day were administered for 3 weeks. Some subjects received a higher dose (LA 800/ALCAR 2000 per day) for an extra 3 weeks to test tolerability. Paired t-test was performed to compare variables at baseline and after 3 weeks. Plasma redox sulfur-amino acids were measured by liquid chromatography/tandem mass spectrometry. The redox state of plasma free glutathione (reduced:oxidized GSH) was significantly better at 3 weeks (14.3±4.9 vs. 18.6±3.9, p=.004). Plasma cysteine, methionine and homocysteine redox ratios were unchanged. Intracellular amino acid profile of RBC was significantly altered by LA/ALCAR. LA is a known inducer of GSH synthesis. There was 4-fold increase in cysteine (p=.027), 1.4-fold increase in glycine (p=.003), and 1.7-fold increase in serine (p=.026), all of which are precursors of GSH. The increase in glutamate (1.3-fold) was not significant. Total red cell GSH content was unchanged, though there was a trend towards better GSH redox (1.5-fold, p=.109). RBC arginine content was significantly higher following therapy (1.7-fold, p=.026). Ornithine decreased slightly (0.87-fold, p=n.s.), and arginine:ornithine ratio increased by 2.1-fold (p=.099). The content of other amino acids did not change significantly. The effect of antioxidant therapy on serum markers of inflammation was examined. CRP was elevated (>8 mg/L) at baseline in 5/10 subjects with SCD (range 9–27 mg/L). CRP returned to normal in 3/5 subjects at the end of 3 weeks. The other two subjects with elevated CRP at baseline developed VOC during the study, which was associated with further rise in CRP. Plasma IL-6, elevated at baseline in one subject (16.2 pg/mL), also returned to normal (0.3 pg/mL). Only 1/5 subjects with a normal CRP at baseline (2.7 mg/L) had a higher level (9.1 mg/L) at the end of study. No significant change in the plasma sVCAM level was noted. IL-1β level was below the limit of detection in all cases. Treatment was well tolerated, except for 1 subject (Hb SC) who dropped out after 1 week following a localized neck rash. Three SCD subjects experienced vaso-occlusive (VOC) pain episodes while on study (2 in week 3, 1 in week 6, including 1 death). No adverse events were recorded in subjects with thalassemia. The data demonstrate that treatment with LA/ALCAR is capable of improving plasma redox status in hemoglobinopathies. There is a beneficial impact on RBC amino acid profile, with increase in GSH precursors and a significant improvement in arginine content. Systemic inflammation appeared to improve in subjects with SCD who did not develop VOC while on study.

Author notes

Disclosure:Ownership Interests: Juvenon (www.juvenon.com) is a company founded by Dr. Bruce N. Ames, Nathan Hamilton, and Dr. Tory Hagen. Juvenon has licensed the University of California patent (Ames and T. Hagen, inventors) on acetyl carnitine plus lipoic acid (two mitochondrial metabolites) for rejuvenating old mitochondria and sells acetyl carnitine plus lipoic acid supplements. Ames founder’s stock in Juvenon is in a nonprofit foundation, and he has no other stock and does not receive any remuneration from them. Membership Information: Dr Ames serves on the Scientific Advisory Committee of Juvenon.