Publication Date:
2018-11-29
Description:
Introduction: Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department visits and hospitalization in patients with sickle cell disease (SCD). There is currently no standard therapy for treating the underlying causes of VOE; supportive care & symptomatic pain relief with parenteral opioids is the mainstay of therapy. Prior work by Morris & colleagues has demonstrated that patients in VOE show depleted concentrations of plasma L-arginine (Arg), and that supplementation with Arg significantly decreases total parenteral opioid use and improves pain scores during hospitalization in these patients (Morris et al 2013, Haematologica). The mechanisms by which Arg mediates these positive effects remain unclear, but are potentially due to its ability to modulate metabolism through increased Arg transport or affect vascular signaling through the stimulation of nitric oxide production. The Shiva lab has previously demonstrated that platelet mitochondrial function is altered in patients with SCD compared to healthy controls (Cardenas et al 2014, Blood). This alteration is manifested as a decrease in mitochondrial electron transport Complex V (ATP Synthase) activity, which leads to decreased respiration and increased detrimental oxidant production. Here we hypothesized that treatment of SCD patients in VOE with Arg increases mitochondrial function. Methods: In a pharmacokinetic study, 10 subjects with Hb-SS or Sb0-thalassemia hospitalized for VOE (age 14±3 years, 70% male, 80% Hb-SS) were randomized to treatment utilizing one of 3 dosing schemes of L-arginine: 1) 100mg/kg IV three times/day (n=3); 2) loading dose (200mg/kg) then 100mg/kg three times/day (n=4); or 3) loading dose (200mg/kg) followed by continuous infusion (300mg/kg/day) until discharge (n=3). Platelet rich plasma was isolated & stored at baseline & discharge for each subject & mitochondrial electron transport complex activities, protein expression, as well as protein carbonyls were measured. Results: Compared to a cohort of SCD patients in steady state, all subjects in VOE had a significantly decreased complex V activity (Fig 1A). Notably, complex V activity was increased at discharge in subjects with VOE treated with Arg in all three dosing schemes. However, the increase in complex V activity was greatest when utilizing a loading dose. (Fig 1B, p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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