Buphenyl_ASA

In addition to its role in the urea cycle, argininosuccinate ASL is also essential for endogenous (produced within the body) synthesis of arginine. Patients affected by ASA deficiency can have liver involvement ranging from liver enlargement (hepatomegaly) with elevations of liver enzymes to severe liver fibrosis. The cause for the increased incidence of liver dysfunction in ASA is not known, but has been thought to be due to increased argininosuccinate upstream of the enzymatic block in the urea cycle, or decreased arginine downstream of that block. The standard of care for patients with ASA has historically included arginine supplementation that compensates for the decreased endogenous synthesis in addition to promoting the excretion of nitrogen as argininosuccinic acid.

The investigators hypothesized that if increased levels of argininosuccinic acid were the predominant cause for liver dysfunction, a high dose of therapeutic arginine (500mg/kg/day) would be associated with worsening of liver functions as compared to a low dose of arginine (100mg/kg/day) combined with sodium phenylbutyrate, which would result in lower levels of argininosuccinic acid levels. To evaluate the effects of these two treatments on liver function in patients with ASA, a randomized double-blind placebo controlled cross-over trial was carried out by Dr. Brendan Lee and his team at Baylor as part of the Urea Cycle Disease Consortium research. Eleven patients completed both arms of the trial and were included in the analysis.

As expected, patients had significantly increased levels of phenylacetylglutamine and phenylacetic acid while on low-dose arginine with sodium phenylbutyrate, and higher plasma arginine and citrulline levels while on high-dose arginine. Ammonia control was comparable between the two arms of the trial. Patients had statistically significant increases in plasma ASA levels while on high-dose arginine. AST levels were increased in the high-dose arginine arm. Patients with abnormal liver transaminases seemed to have the most increase in liver enzymes while on high-dose arginine. The function of the liver as assessed by PT, INR, Factors VII, IX and fibrinogen were comparable between the two arms of the study.

These results reveal that high dose arginine may lead to higher liver inflammation in patients with ASA, especially in patients with existing liver dysfunction. The results have therapeutic implications, as they suggest it may be optimal to treat ASA patients who have liver dysfunction with lower doses of arginine combined with nitrogen scavenging therapy with sodium phenylbutyrate.

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all eligible patients, but cannot make any guarantees to enroll everyone in a particular study who wants to participate.

This is a study to determine if treatment of argininosuccinic aciduria (ASA) patients with sodium phenylbutyrate (Buphenyl TM) along with low arginine improves outcomes. Our goal is to study 12 participants with ASA. Unlike the other urea cycle disorders, ASA can lead to serious liver damage. The cause of this liver damage is not known, but since high levels of argininosuccinic acid are found in this disease and not in the other urea cycle disorders, doctors suspect this may be the cause of the liver damage.

Through this study we hope to learn how the use of sodium phenylbutyrate (Buphenyl-TM) and low dose arginine, along with a restricted-protein diet, affects liver activity in patients with ASA. We will also study how this treatment compares to therapy with high-dose arginine alone in affecting how well an individual with ASA is able to change nitrogen into nitric oxide and urea. Our goal is to help doctors and researchers find out more about how to best treat individuals with ASA.

Those participating will be evaluated during two separate in-patient visits conducted at Texas Children’s Hospital in Houston, Texas.

Be at least 5 years old with a confirmed diagnosis of ASA.
Agree to travel to Baylor College of Medicine in Houston, Texas.
Maintain the diet and treatment plan prescribed by Dr. Brendan Lee while you are in the study

You are not eligible to participate if:

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.
Is pregnant or lactating.
Is 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.
Known hypersensitivity to sodium phenylbutyrate.
Has taken any experimental medication within the last 30 days.
Has renal insufficiency with creatinine > 1.5 mg/dl at screening.

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

5102: The Effect of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)