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According to data presented at the ASH 2022 Annual Meeting, this is the first suggestion of a hydroxyurea-related impact on mito activity in patients with sickle cell disease.
Individuals with sickle cell disease (SCD) present at the emergency department (ED) and are often admitted for hospitalization most commonly for vaso-occlusive pain episodes (VOEs). These episodes, also referred to as "pain crises" due to the intense pain experienced by patients, cause an acute arginine (Arg) deficiency.
Arg supplementation has shown positive impacts on blood pressure, cardiopulmonary function, and has decreased the length of patients' hospital stay. With supplementation, patients often require lower doses of opioids to manage the episode.
Previous research demonstrated intravenous (IV) Arg improves mitochondrial (mito) function. Beyond this, not much is understood about the precise mechanisms that enable Arg to mediate such benefits in this patient population.
This morning at the American Society of Hematology (ASH) Annual Meeting and Exposition, Claudia Morris, MD, Childrens Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, presented her team's findings regarding the role of Arg in the management of vaso-occlusive episodes in patients with sickle cell disease.
The prospective, single-center, double-blind, randomized controlled trial included children and young adults between the ages of 3-21 with sickle cell disease. The participating patients were enrolled if they were hospitalized for a VOE and required IV opioid treatment. Those with significant liver or renal dysfunction, or who had previously been enrolled were excluded.
Patients were randomized to receive either the standard dose of 100 mg/kg Arg; loading dose of 200 mg/kg; or placebo. Before treatment and at the time of discharge the following patient data were obtained: demographics, total parenteral opioid (TPO) use (morphine equivalents, mg/kg) time to crisis resolution (time of study drug delivery to last IV opioid in hours), pain scores, patient reported outcomes (PROMIS) and mito function.
The primary outcome of the investigation was the total parenteral opioid use compared between each study groups. To assess cross-sectional and longitudinal outcomes within and across groups, investigators implemented hypothesis tests, unadjusted and covariate-adjusted fixed and mixed effects, and generalized linear regression models.
Results demonstrated mito activity increased, while oxidative stress decreased in the children and young adults who received Arg supplementation. According to investigators, this study is the first to suggest a hydroxyurea-related impact on mito activity in this population.
After screening a total of 1548 patients, 108 were randomized. Emergency department and discharge pain scores, as well as patient/parent reported outcomes, didn't exhibit any differences across the study groups. However, patients on hydroxyurea had higher mito complex V activity, and lower protein carbonyl levels during time in emergency deparment.
Investigators emphasized the increases in mito Complex IV & V activity observed in both study groups that received Arg supplementation (with the greatest improvement occurring with the Arg loading dose), while there was no change in the placebo group. Additionally, protein carbonyl levels in platelet rich plasma decreased in both Arg groups, which suggested a decrease in oxidative stress that increased in the placebo arm.
When assessing children under the age of 17, those in the placebo group (n=33) required 80% more total parenteral opioid compared to combined Arg groups (n=57)
While statistically insignificant, investigators acknowledged a clinically relevant decrease in total parenteral opioid, and a shortened time to crisis resolution in both Arg groups compared to placebo. The placebo group experienced a mean of 15 or more additional hours to crisis resultion compared with the intervention groups, and required 45% higher TPO, after adjustments for hydroxyurea use, continuous age and sex.
"Arg therapy improves symptoms associated with MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) suggesting an impact of Arg on mito activity that may be beneficial in SCD," investigators wrote. "Given emerging data supporting a link between mito function and pain, improved mito activity may mechanistically contribute to decreased pain and ultimately less opioid requirement with IV Arg treatment, as well as have further implications for improved metabolism and oxidative signaling in SCD."