Sickle cell anemia or drepanocytosis is one of the most common hemoglobinopathies in the world; and episodes of vaso-occlusive pain are the main cause of hospitalizations and visits to the emergency room. There are limited therapies for the management of acute attacks, which directly target the underlying etiology of sickle-related pain; therefore, treatment is largely symptomatic. Moderate to severe pain is typically treated with parenteral hydration, opioids, and hospitalization to achieve adequate pain control. Glutamine is a non-essential amino acid that was recently approved as a supplement (under the name Endari) for the control of clinical symptoms and to prevent vascular episodes. Very recently, data has been released that vitamin B6 (pyridoxamine) could become another safe and useful supplement to treat this condition. Now it looks like it’s the turn of arginine, another amino acid. Arginine is a semi-essential amino acid and a required substrate for the synthesis of the radical nitric oxide (*NO).
NO is a potent vasodilator, essential for the vascular system, but its low bioavailability contributes to sickle cell vasculopathy. IV arginine therapy has been used successfully in the treatment of multiple medical conditions including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), acute metabolic strokes in mitochondrial diseases (e.g. Kearns-Sayre syndrome ) and hyperammonaemic crises due to defects in the urea cycle. Sicklemia is an arginine-deficient syndrome in which low bioavailability of arginine correlates with the risk of pulmonary hypertension, early mortality, and pain severity, predicting the need for pediatric hospitalization. Arginine is also a precursor of kyotorphine (L-tyrosyl-L-arginine), an endogenous analgesic peptide similar to endorphins. Intravenous arginine therapy was found to reduce opioid use by more than 54%. It significantly reduces pain scale scores in hospitalized children compared to placebo, as seen in a randomized, phase 2, double-blind, placebo-controlled trial (RCT).
A recent RCT of oral arginine therapy in children hospitalized for SCD-VOE in Nigeria similarly found a reduction in total analgesia, pain scores, time to resolution of seizures, and total length of hospital stay. Intravenous arginine has an excellent safety profile, having received FDA approval for growth hormone stimulation tests in 1973, using 500 mg / kg / dose (maximum 30 g / dose) over 30 minutes. IV arginine has also been used in the management of mitochondrial disease and sepsis with few side effects. Side effects reported with the use of IV arginine include nausea, vomiting, headache, flushing, dyspnoea, and dose-dependent effects on blood pressure, electrolytes (e.g. potassium), and acid-base imbalance. These, however, can only appear after prolonged use. A Phase 2 RCT evaluating two IV arginine dosing regimens at Emory Children’s Healthcare in Atlanta completed enrollment of volunteer subjects for treatment late last year.
Multiple parameters such as serum bilirubin, AST and ALT (transaminases and marker of hemolysis) were monitored during the study. They were elevated at randomization in some patients and increased after treatment, but there were no significant differences between treatment arms in adverse events of total liver function or those that occurred after treatment. Of particular interest in this study was the discovery of elevated serum ALT transaminase levels in some patients prior to randomization, which continued to increase over the course of the study. This is unlikely to be related to intravenous administration of arginine as it was observed in all three arms of the cohort; it could instead represent the normal course, not previously described, of hepatic dysfunction during painful crises. Although statistically significant differences were observed between the study arms in serum urea nitrogen, bicarbonate and potassium, these were not clinically relevant.
Overall, the results of the trial were satisfactory and the researchers believe that arginine can be used safely to treat and / or prevent vascular crises in sickle-stricken children. Arginine is an amino acid that our body is also able to synthesize; its dietary supplementation is contemplated among sportsmen, health enthusiasts and among those who have medical conditions affecting the skeletal or heart muscle. Aside from supplements, there are types of foods whose proteins are richer in arginine than others. But there are no studies on the possibility of a dedicated diet rich in arginine to be applied to patients with sickle cell disease, at least to date.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Reyes LZ et al. Amer J Hematol 2022; 97(1):21-24.
Onalo R et al. Amer J Hematol. 2021; 96(1): 89-97.
Morris CR et al. Haematologica 2013; 98(9):1375-82.
Morris CR, Kato GJ et al. JAMA. 2005; 294(1):81-90.
Dott. Gianfrancesco Cormaci
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