When stored overnight, all paired pre-IVIG and 24 hour post-IVIG samples per patient were stored for uniform lengths of time

When stored overnight, all paired pre-IVIG and 24 hour post-IVIG samples per patient were stored for uniform lengths of time. IVIG can decrease Mac-1 function. strong class=”kwd-title” Keywords: sickle cell anemia, vaso-occlusion, pain crisis, Mac-1, intravenous gammaglobulin Introduction In murine models of sickle cell acute pain crisis, intravenous immunoglobulin (IVIG) reduces neutrophil adhesion to post capillary venular endothelium and adherent neutrophil interactions with circulating red blood cells (RBCs), thus increasing microcirculatory blood flow and survival.[1, 2] These effects were observed at IVIG doses between 200C800 mg/kg as early as 20 minutes after IVIG administration.[1, 2] While neutrophil rolling and adhesion are mediated via P and E-selectins on endothelium, E-selectin ligand-1 and Src family kinase activation mediate a secondary wave of signals polarizing activated Mac-1 (M2) on the leading edge of neutrophils, with subsequent capture of sickle RBCs.[3] IVIG inhibits Mac-1 dependent RBC capture by Propineb binding to the activating Fc receptor FcRIII on neutrophils, resulting in recruitment of the protein tyrosine phosphatase SHP-1 to FcRIII and subsequent inhibition of activated Mac-1.[4] The potentially important role of neutrophil adhesion and sickle RBC capture in sickle cell mouse models of acute pain crisis has recently been supported Propineb by the success of the Phase II trial of the pan-selectin inhibitor GMI-1070 in reducing time to resolution of pain crisis and opioid use[5C7]. We conducted a Phase I study of the safety and effect on neutrophil activation status of IVIG administered, owing to its long half-life, as a single-dose infusion upon hospital admission for acute pain crisis. Methods Study design and conduct A Phase I randomized, double-blind, dose-finding study of IVIG (Gamunex-C, Grifols, Clayton, NC) was conducted in children and adults with Hb SS or S0-thalassemia requiring hospital admission for uncomplicated (unaccompanied by infection or other acute processes) acute pain crisis between January 2009 and December 2013. The study took Propineb place at 2 collaborating hospitals, The Mount Sinai and Montefiore Medical Centers. Gamunex-C is hypo-osmolar (258 mOsm/kg), sucrose-free, and contains only trace amounts of sodium, and thus has Rabbit Polyclonal to PRIM1 an excellent risk profile with regard to volume overload/renal toxicity.[8, 9] 15 subjects were randomized by pharmacy staff using a computer-generated randomization algorithm to a total of 20 acute pain crises at a ratio of 3 IVIG: 1 equivalent-volume normal saline control at each dosing cohort of 100, 200, 400, 600, and 800 mg/kg IVIG (a modified Fibonacci dose escalation design). Propineb Subject re-enrollment at subsequent dosing levels occurred in 3 subjects after a 3-month washout period. Study drug was administered as soon as logistically feasible after inpatient admission. Actual patient weight was used for dose calculation. Standard-dose oral acetaminophen and diphenhydramine pre-medication, as well as bolus opioids as needed with single line availability, was administered and then study drug/placebo was infused undiluted (100 mg/mL) at the recommended manufacturer rate (starting at 1 mg/kg/min up to 8 mg/kg/min for dosing cohorts 100, 200 and 400mg/kg, up to 4mg/kg/min for 600mg/kg, and over 6 hours for 800mg/kg). Clinicians (including investigators) and patients were blinded to treatment by masking of the infusion bag and tubing by pharmacy staff. Outpatient hydroxyurea (HU) dosing was continued during the hospitalization. Pain was managed with morphine or hydromorphone patient controlled analgesia adjusted per usage and the FACES or numeric rating scales at least every 8 hours throughout the hospital stay by anesthesiologist co-investigators. The non-steroidal anti-inflammatory drugs ibuprofen or ketorolac were also allowed, but there was no significant difference in their usage rate between groups. Subcutaneous heparin prophylaxis was administered to adult patients per routine standard at Mount Sinai, but was not administered to pediatric patients at Montefiore. A Data Safety and Monitoring Board approved progression to the next cohort after completion of each dosing cohort. Stopping rules for study hold pending IRB review were 2 unexpected possibly-related Grade 3 severe adverse events (SAE), 1 unexpected possibly-related thrombo-embolic event, or 1 unexpected possibly-related Grade 4C5 SAE. The study was institutional review board approved at all sites, and written informed consent was obtained from all subjects. All investigators involved in data collection and analysis had access to primary clinical trial data. The trial is registered as Intravenous Gamma globulin for Sickle Cell Pain Crisis under the ClinicalTrials.gov identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01757418″,”term_id”:”NCT01757418″NCT01757418. Study subjects Inclusion criteria were as follows: SS or S0-thalassemia sickle cell disease genotype; age 8C65 years for dosing cohorts up to 400mg/kg and 12C65 years for subsequent dosing cohorts; normal stroke.