Valproic Acid-associated Hypoalbuminemia in Medically Fragile Patients

Hypoalbuminemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00723762
• Other study ID #: Valproic Acid-Albumin
• Status: Completed
• Phase: N/A
• First received: July 25, 2008
• Last updated: March 8, 2011
• Start date: February 2009
• Est. completion date: December 2010

Study information

• Verified date: March 2011
• Source: Akron Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: December 2010
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Observational Model: Case Control

Related Conditions & MeSH terms

• Hypoalbuminemia

Intervention

Procedure:
• Specimen collection
A blood sample and a spot urine sample will be obtained from all eligible patients receiving VPA at the start of the study.

Locations

Country	Name	City	State
United States	Hattie Larlham Center for Children with Disabilities	Mantua	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Akron Children's Hospital

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

Castro-Gago M, Rodrigo-Saez E, Novo-Rodriguez I, Camiña MF, Rodriguez-Segade S. Hyperaminoacidemia in epileptic children treated with valproic acid. Childs Nerv Syst. 1990 Dec;6(8):434-6. — View 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. — View 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. — View 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. — View Citation

Rugino TA, Janvier YM, Baunach JM, Bilat CA. Hypoalbuminemia with valproic acid administration. Pediatr Neurol. 2003 Nov;29(5):440-4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome will be serum albumin concentrations at baseline in the patients receiving VPA.		Baseline	Yes
Secondary	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.		Baseline	No