Clinical trial NCT00723762: Valproic Acid-associated Hypoalbuminemia in Medically Fragile Patients
Official title: Valproic Acid-associated Hypoalbuminemia in Medically Fragile Pediatric and Young Adult Patients in a Long Term Care Facility Part 1: Potential Mechanism for Decreased Albumin Synthesis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hypoalbuminemia
Keywords: Valproic acid
Urea cycle
Ornithine
Valproate
Side effect
Lead sponsor: Akron Children's Hospital
Sponsor class: OTHER
First posted: 2008-07-29
Enrollment: 90
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Medically fragile residents of the Hattie Larlham Long Term Care Facilit.

Brief summary: The purpose of this study is to investigate potential mechanisms of valproic acid-associated low serum albumin in medically fragile pediatric and young adult epileptic patients of a long-term care facility.

Detailed description: Valproic acid (VPA) is a long-chain fatty acid frequently used as an antiepileptic agent in pediatric and adult seizure patients. Other adverse effects that have been associated with VPA use include hepatic steatosis, altered mitochondrial function and decreased concentrations of serum proteins. The exact mechanism or mechanisms by which VPA induces these associated adverse drug effects are not fully understood though multiple theories have been postulated including impaired vesicle transport within the hepatocyte, inhibition of hepatic synthetic metabolic pathways and renal protein loss. Decreased serum albumin concentrations with concomitant VPA use have been identified in multiple studies. Albumin synthesis is sensitive to tryptophan concentrations (other amino acids are also able to stimulate albumin synthesis), oncotic pressure near the synthetic site, and energy supply while albumin release from the hepatocyte is sensitive to intrahepatocellular potassium concentrations. Based on available literature, VPA appears to inhibit an enzyme(s) either directly or indirectly involved with albumin synthesis or albumin gene expression. VPA is known to inhibit the urea cycle, including patients with ornithine-transcarbamylase (OTC) deficiency, possibly by inhibiting mitochondrial carbamoyl-phosphate synthase. Oratz et al discussed the potential correlation between the urea cycle and albumin synthesis identified after the administration of various amino acids increased both albumin and urea synthesis. Ornithine is an intermediate amino acid within the urea cycle and it is also a precursor to polyamines which have been shown to increase the degree of aggregation of polysomes, responsible for protein synthesis, bound to the endoplasmic reticulum. Thus, VPA may indirectly inhibit protein synthesis by interfering with the urea cycle leading to decreased ornithine concentrations and subsequently a decrease in polyamine concentrations and a decrease in the number of bound polysomes resulting in alterations in albumin synthesis and release. The purpose of this study is to investigate potential mechanisms of VPA-associated hypoalbuminemia in medically fragile pediatric and young adult epileptic patients of a long-term care facility.

Eligibility criteria: Inclusion Criteria:

* Resident of Hattie Larlham long-term care facility receiving VPA for \> 3 months at the start of the study
* Resident of Hattie Larlham long-term care facility matched to a resident receiving VPA for \> 3 month based on concomitant AED, length of time on AED, age, and gender
* Resident of Hattie Larlham long-term care facility not receiving AED matched to a resident receiving VPA for \> 3 month based on age and gender

Exclusion Criteria:

* Received albumin products within the past 1 month
* Receiving VPA for \< 3 months or discontinuation of VPA therapy within the past four weeks
* Medical need for specific protein supplementation
* Diagnosed with protein-losing nephropathy or enteropathy

Primary outcomes:
measure: The primary outcome will be serum albumin concentrations at baseline in the patients receiving VPA.
timeFrame: Baseline
Secondary outcomes:
measure: Secondary outcome variables will include serum amino acid concentrations, total protein, AST, ALT, alkaline phosphatase, ammonia, BUN, and sCr and urine albumin, protein, and urea.
timeFrame: Baseline
Other outcomes:
Locations:
city: Mantua
country: United States
facility: Hattie Larlham Center for Children with Disabilities
state: Ohio
Study officials:
affiliation: Akron Children's Hospital Research Center
name: Michael Reed, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Akron Children's Hospital
name: Martha Blackford, PharmD
role: STUDY_CHAIR
affiliation: Hattie Larlham
name: Richard Grossberg, MD
role: STUDY_CHAIR
References:
citation: Attilakos A, Voudris KA, Katsarou E, Prassouli A, Mastroyianni S, Garoufi A. Transient decrease in serum albumin concentrations in epileptic children treated with sodium valproate monotherapy. Clin Neuropharmacol. 2007 May-Jun;30(3):145-9. doi: 10.1097/wnf.0b013e3180318a99.
citation: Hauser E, Seidl R, Freilinger M, Male C, Herkner K. Hematologic manifestations and impaired liver synthetic function during valproate monotherapy. Brain Dev. 1996 Mar-Apr;18(2):105-9. doi: 10.1016/0387-7604(95)00139-5.
citation: Rugino TA, Janvier YM, Baunach JM, Bilat CA. Hypoalbuminemia with valproic acid administration. Pediatr Neurol. 2003 Nov;29(5):440-4. doi: 10.1016/s0887-8994(03)00310-2.
citation: Oratz M, Rothschild MA, Schreiber SS, Burks A, Mongelli J, Matarese B. The role of the urea cycle and polyamines in albumin synthesis. Hepatology. 1983 Jul-Aug;3(4):567-71. doi: 10.1002/hep.1840030415.
citation: Karikas GA, Schulpis KH, Bartzeliotou A, Karakonstantakis T, Georgala S, Kanavaki I, Demetriou E, Papassotiriou I. Lipids, lipoproteins, apolipoproteins, selected trace elements and minerals in the serum of children on valproic acid monotherapy. Basic Clin Pharmacol Toxicol. 2006 Jun;98(6):599-603. doi: 10.1111/j.1742-7843.2006.pto_402.x.
citation: Castro-Gago M, Rodrigo-Saez E, Novo-Rodriguez I, Camina MF, Rodriguez-Segade S. Hyperaminoacidemia in epileptic children treated with valproic acid. Childs Nerv Syst. 1990 Dec;6(8):434-6. doi: 10.1007/BF00302087.