STANFORD, Calif. -- Treating inborn urea-cycle disorders with intravenous phenylacetate and benzoate, an alternative way to remove toxic ammonia, has saved more than 80% of patients, mainly children, researchers here reported.
STANFORD, Calif., May 31 -- Treating inborn urea-cycle disorders with intravenous phenylacetate and benzoate, an alternative way to remove toxic ammonia, has saved more than 80% of patients, mainly children, researchers here reported.
Survival ranged from 73% for neonates to 98% for those older than 30 days, according to a 25-year, open-label, uncontrolled study of phenylacetate and benzoate therapy, Gregory M. Enns, M.B., Ch.B., of Stanford, and colleagues, reported in the May 31 issue of the New England Journal of Medicine.
An alternative ammonia disposal was proposed in 1979 and since that time this therapy has been more commonly used to treat patients with acute hyperammonemia than hemodialysis and exchange transfusions, they said.
The study included survival data on 299 patients (neonates, infants, children, and those 12 or older) with urea-cycle disorders who were hospitalized at 118 hospitals in the U.S. and Canada from 1980 to 2005.
Patients were treated with an IV phenylacetate-benzoate drug containing both compounds (Ammonul), supplied by its maker, Ucyclyd Pharma.
Of the patients, 164 had ornithine transcarbamylase deficiency and the next most frequent diagnosis was argininosuccinate synthetase deficiency for 80 patients.
When the urea-cycle enzymes are defective or deficient due to a metabolic disorder, these inborn errors disrupt the normal processing of ammonia from catabolism of amino acids into urea and result in hyperammonemia, the researchers said.
The alternative disposal approach uses endogenous biosynthetic pathways to eliminate non-urea-waste nitrogen as a substitute for defective urea synthesis. In theory the total body load of nitrogen can be decreased by promoting synthesis of non-urea-containing metabolites that have high excretion rates or rates that may be augmented, the researchers wrote.
Not surprisingly, patients were more likely to survive if they were not comatose at the time of admission. Yet 81% of the comatose patients survived, the researchers reported.
Adverse events -- anemia, metabolism and nutrition disorders, cardiac or nervous system disorders, for example -- were reported in just over 50% of treated patients. However, most of these events were likely related to the underlying primary disease or the patient's clinical status.
Various neurologic outcomes among patients given the alternative-pathway treatment have been documented. In this study of 23 neonatal survivors, 10 had normal development, seven had mild mental retardation, and six had moderate-to-severe mental retardation.
Nevertheless, the researchers said, normal intelligence is clearly possible after a hyperammonemic event and appears to depend on the duration of coma and the extent of brain damage.
"We think that timely administration of alternative-pathway therapy may reduce or eliminate the need for hemodialysis, depending on the level and duration of the hyperammonemia, the stage of coma, and the presence or absence of brain edema, but prospective, multicenter trials involving patients of all ages are needed to address the role of hemodialysis further," the researchers wrote.
Although survival among patients with urea-cycle disorders has clearly improved, they added, overall neurologic outcomes remain to be evaluated in detail.
In an accompanying editorial, Vivian E. Shih, M.D., of Massachusetts General Hospital in Boston, wrote that "clearly, alternative-pathway therapy has improved the survival of patients with urea-cycle disorders." However, she said, neurologic outcome was not evaluated in this study.
"This report of such a large group of patients treated over a long period is an important first step in the development of improved treatments for patients with urea-cycle disorders," Dr. Shih said.
Standardized treatment protocols with long-term follow-up and evaluation of neurologic outcome are important for the future, she added.
Ucyclyd supplied the study drug and provided access to its database for urea-cycle patients. This study was supported in part by grants from the General Clinical Research Centers at Johns Hopkins University, Children's Hospital of Philadelphia, and Children's National Medical Center; other grants from the U.S. Public Health Service, National Institute of Child Health and Human Development, and the Food and Drug Administration; and the National Center for Research Resources during early phases of this study, through support of the National GCRC network. Dr. Shih, the editorialist, reported no conflict of interest relevant to this article.