Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury
Condition: Pediatric Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The overall purpose of this research study is to investigate the safety of pharmacological
      therapies that may potentially improve pediatric outcomes after traumatic brain injury.
      Traumatic brain injuries are the leading cause of death and disability among children and
      young adults.

      Hypothesis: Combinational therapy with a membrane transporter and antioxidant are safe after
      TBI and can overcome barriers to the brain and synergistically improve bioavailability and
      efficacy the antioxidant content of the body and CNS after TBI.
    

Detailed description: 
      Specific Aim: Define the capacity of the combination of probenecid and NAC to safely and
      synergistically preserve levels of GSH and reduce oxidative stress in children with severe
      TBI. We will enroll 20 children age 2 to less than 18 years old (less than 216 months) after
      severe TBI in a randomized, controlled study of administration of the combinational therapy
      and test if the administration of these drugs is safe and if antioxidant reserve can be
      preserved within the serum and CSF.

      Probenecid (at the same dose that is used as an adjunct to antibiotic therapy) and NAC (at
      the same dose that is used for acetaminophen-induced liver disease), or vehicles will be
      given for 3 days. The primary outcomes of the study will be the safety of drug administration
      and the CSF and serum levels anti-oxidant reserve (AOR), with the presumption that
      maintaining anti-oxidant levels within the brain may prove neuroprotective. Other secondary
      outcomes (CSF and serum probenecid, NAC, GSH and phenytoin concentrations) will also be
      tested. Adverse events occuring during treatment with these drugs after TBI will be monitored
      by a local Data Safety Monitoring Board.
    

Intervention name(s): Probenecid and N-acetyl cysteine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.; After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Other intervention name(s): Ora Plus
Intervention MeSH terms: Acetylcysteine; Probenecid; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Children; Brain injury; Trauma