Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder

The cause of liver damage in people with ASA is unknown. However, because ASA is the only urea cycle disorder that is characterized by both liver damage and elevated levels of argininosuccinic acid, researchers believe that the elevated acid levels cause the liver damage. Common treatments for urea cycle disorders include a low-protein diet and arginine supplementation, which, when combined, help to decrease ammonia levels in the blood. Buphenyl-TM may aid in lowering ammonia and argininosuccinic acid levels. Although Buphenyl-TM has been FDA-approved for use in people with some types of urea cycle disorders, there is little information on the effectiveness of the drug in children with ASA. This study will evaluate whether treatment of ASA patients with Buphenyl-TM in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production.

Initially, participants in this double-blind, placebo-controlled, crossover study will undergo a 3-day washout period during which no Buphenyl-TM will be given. They will then be randomly assigned to one of two groups: either Buphenyl-TM (500 mg/kg/day or 10 grams/m2) and arginine (100 mg/kg/day or 2 grams/m2)), or arginine alone (500 mg/kg/day or 10 grams/m2). Participants will remain on this initial treatment arm for 1 week, at the conclusion of which an assessment of hepatic synthetic function, ureagenesis, and nitric oxide production will be performed. After this assessment, participants will undergo a second 3-day washout and then crossover to the other treatment arm for 1 week. At the end of the 1-week treatment period, a second assessment will be performed. During the washout period before each treatment period, no Buphenyl-TM will be administered, and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/2.

Inclusion criteria

• Has confirmed diagnosis of ASA by amino acid or enzyme assay
• Has a history of adequate compliance to the diet and treatment
• Able to take oral or G-tube medication
• Able to perform 24 hour urine collection
• Agrees to travel to Baylor College of Medicine
• If female, of child bearing potential, and sexually active, agrees to use an acceptable method of birth control
• Greater than 5 years of age

Exclusion criteria

• Has a history of congestive heart failure, severe renal insufficiency, or any condition that causes sodium retention or edema
• Currently taking Probenecid, Haloperidol, Valproate or oral corticosteroids
• Pregnant or lactating
• Currently being treated for an acute illness
• Has co-morbid associations causing difficulties in the detection of hyperammonemic episodes, liver damage, or difficulties in the diet compliance
• Has known hypersensitivity to sodium phenylbutyrate
• Has taken any experimental medication within the last 30 days
• Has renal insufficiency with creatinine greater than 1.5 mg/dl at screening