Valproic Acid-associated Hypoalbuminemia in Medically Fragile Patients

This study has been completed.
Sponsor:
Information provided by:
Akron Children's Hospital
ClinicalTrials.gov Identifier:
NCT00723762
First received: July 25, 2008
Last updated: March 8, 2011
Last verified: March 2011
  Purpose

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.


Condition Intervention
Hypoalbuminemia
Procedure: Specimen collection

Study Type: Observational
Study Design: Observational Model: Case Control
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

Resource links provided by NLM:


Further study details as provided by Akron Children's Hospital:

Primary Outcome Measures:
  • The primary outcome will be serum albumin concentrations at baseline in the patients receiving VPA. [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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. [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Serum and urine samples from patients receiving VPA.


Estimated Enrollment: 90
Study Start Date: February 2009
Study Completion Date: December 2010
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
1
Resident of Hattie Larlham long-term care facility receiving VPA
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.
2
Control AED patients will be recruited based on similar AED regimens excluding VPA, length of time on AED (number of months to >1 year), age, and gender; one control patient per VPA patient.
3
Control non-AED patients will be recruited based on age and gender; one control patient per VPA patient.

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

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Medically fragile residents of the Hattie Larlham Long Term Care Facilit.

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00723762

Locations
United States, Ohio
Hattie Larlham Center for Children with Disabilities
Mantua, Ohio, United States, 44255
Sponsors and Collaborators
Akron Children's Hospital
Investigators
Principal Investigator: Michael Reed, PharmD Akron Children's Hospital Research Center
Study Chair: Martha Blackford, PharmD Akron Children's Hospital
Study Chair: Richard Grossberg, MD Hattie Larlham
  More Information

Publications:
Responsible Party: Michael Reed, Pharm.D., Akron Children's Hospital
ClinicalTrials.gov Identifier: NCT00723762     History of Changes
Other Study ID Numbers: Valproic Acid-Albumin
Study First Received: July 25, 2008
Last Updated: March 8, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Akron Children's Hospital:
Valproic acid
Urea cycle
Ornithine
Valproate
Side effect

Additional relevant MeSH terms:
Hypoalbuminemia
Hypoproteinemia
Blood Protein Disorders
Hematologic Diseases
Valproic Acid
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs

ClinicalTrials.gov processed this record on July 29, 2014