The purpose of this study is to determine whether giving extra arginine to patients with sickle cell disease seeking treatment for vaso-occlusive painful events (VOE) will decrease pain scores, decrease need for pain medications or decrease length of hospital stay or emergency department visit.
Arginine is a simple amino acid that is found in many foods and is part of the proteins in a human's body. Patients with sickle cell disease have low levels of the amino acid arginine and these low levels may be related to pain episodes. Increasing levels of arginine in the blood may lower pain and/or lower the amount of pain medication (like morphine) that is needed to treated them. It may also decrease the amount of time spent in the hospital. Available data suggest that, L-arginine is a safe \& efficacious intervention with narcotic-sparing effects in pediatric SCD patients with VOE. The addition of a higher loading dose to the standard dose or use of a continuous infusion may provide additional clinical benefits by overcoming multiple mechanisms that limit global arginine bioavailability in SCD.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Arginine will be dispensed intravenously (in the vein) in the standard dose of arginine as 100 mg/kg three times a day for seven days or until discharge. * Loading dose: 200 mg/kg once * Continuous IV: 300 mg/kg/24 hours
Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.
Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr
Children's Healthcare fo Atlanta at Hughes Spalding
Atlanta, Georgia, United States
RECRUITINGChildren's Healthcare of Atlanta at Arthur M. Blank Hospital
Atlanta, Georgia, United States
RECRUITINGPharmacokinetics of IV arginine, measured by plasma arginine concentration over time
Total time plasma arginine levels are maintained above the half-saturating concentration (Km) of cationic amino acid transporter protein-1 (CAT-1), which is 150 µM (normal range of extracellular plasma arginine concentration). pK samples will be collected at 6 time-points within 8 hours: prior to arginine treatment (time 0), and at 60, 90, 120 minutes, 4 and 8 hours after the initiation of arginine therapy, and then every 24 hours up to 7 days.
Time frame: Day 1 through study completion, an average of up to 7 days
Change in nitric oxide metabolites
The formation of NO metabolites will be measured by determination of its stable end products in serum; nitrite (NO2-) and nitrate (NO3-). Change in nitric oxide metabolites will be calculated as the difference in metabolites from the time prior to arginine treatment (baseline) to the end of the intervention period.
Time frame: Baseline, day 1 through study completion, an average of up to 7 days
Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine
AUC is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body. AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\])
Time frame: Day 1
Maximum observed plasma concentration of arginine
Maximum measured concentration of the arginine in plasma
Time frame: Day 1
Apparent clearance of arginine
The clearance of a drug measures the rate at which the drug is removed from the body after the dose. Clearance of arginine after intravenous administration on day 1.
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Time frame: Day 1
Terminal elimination half-life (t1/2) for arginine
Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: Day 1
Change in red blood cell (RBC) arginine
Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.
Time frame: Baseline, day 1 through study completion, an average of up to 7 days
Daily urine arginine
Total amount of arginine excreted in urine daily
Time frame: From Day 1 until study completion, an average of up to 7 days
Global arginine bioavailability (GABR)
GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline \[arginine/(ornithine+citrulline)\].
Time frame: From enrollment through study completion, an average of up to 7 days
Change in asymmetric dimethylarginine (ADMA) levels
ADMA is is a metabolic by-product of continual protein modification processes and interferes with L-arginine in the production of nitric oxide. Change in ADMA levels will be calculated as ADMA levels at the end of arginine administration minus ADMA levels at baseline.
Time frame: Baseline, day 1 and through study completion, an average of up to 7 days
Modeling nitric oxide (NOx) level versus plasma arginine level
Modeling nitric oxide (NOx) level versus plasma arginine level will be measured.
Time frame: From enrollment through study completion, an average of up to 7 days
Biomarkers of hemolysis
Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.
Time frame: From enrollment through study completion, an average of up to 7 days
Erythrocyte glutathione levels
Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.
Time frame: From enrollment through study completion, an average of up to 7 days
Level of cytokines
Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.
Time frame: From enrollment through study completion, an average of up to 7 days