Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis

Abstract

We studied the effect on ureagenesis of a single dose of N-carbamylglutamate (NCG) in healthy young adults who received a constant infusion (300 min) of NaH13CO3. Isotope ratio-mass spectrometry was used to measure the appearance of label in [13C]urea. At 90 minutes after initiating the H13CO3− infusion each subject took a single dose of NCG (50 mg/kg). In 5/6 studies the administration of NCG increased the formation of [13C]urea. Treatment with NCG significantly diminished the concentration of blood alanine, but not that of glutamine or arginine. The blood glucose concentration was unaffected by NCG administration. No untoward side effects were observed. The data indicate that treatment with NCG stimulates ureagenesis and could be useful in clinical settings of acute hyperammonemia of various etiologies.

Carglumic acid for the treatment ofN-acetylglutamate synthase deficiency and acute hyperammonemia

“…To judge the efficacy of carglumic acid, some controlled experimental studies addressing the rate of ureagenesis, as measured by isotope investigations in humans, are of high interest [28,61,64]. Here, it was demonstrated that carglumic acid markedly enhances the rate of urea production both in control subjects (n = 17) and normalized urea production in two patients with NAGSD and PA, respectively.…”

“…The use of carglumic acid for treatment of acute hyperammonemia secondary to organic acidurias has been reported in a small number of case reports [26][27][28][29][30]51,52,65] and was also discussed based on isotope studies in healthy volunteers [64]. Most published reports on neonatal patients with MMA or PA describe carglumic acid doses ranging from 100 to 250 mg/kg bw resulting in a rapid decrease of plasma ammonia levels [26,27,29,51,52,[65][66][67].…”

“…The main reasons for this are the dramatic circumstances of any hyperammonemic decompensation often requiring parallel action, which impede identification of patients, inclusion into a clinical study and the comparison of accompanying treatment modalities. As a result, the decision on the use of carglumic acid must be based on theoretical considerations, the reported experience in a small number of patients and on functional studies measuring ureagenesis [28,50,64,68]. Nevertheless, there is still an emerging need to further verify the current knowledge on the role of carglumic acid in controlled studies.…”

Augmenting Ureagenesis in Patients with Partial Carbamyl Phosphate Synthetase 1 Deficiency with N-carbamyl-l-glutamate

“…Studies were performed as previously described (11, 12) (Figure 1; available at www.jpeds.com). This trial measures ureagenesis by monitoring the conversion of administered [1- 13 C]acetate to [ 13 C]urea using ion ratio mass spectrometry.…”

Precision medicine in rare disease: Mechanisms of disparate effects of N -carbamyl- l -glutamate on mutant CPS1 enzymes

“…NCG was also used successfully to treat the hyperammonemia caused by mitochondrial carbonic anhydrase VA deficiency [30]. Because of its low toxicity and significant enhancement of ureagenesis in several metabolic disorders [31,32], a therapeutic trial with NCG has been proposed in any patient with undiagnosed hyperammonemia [33,34]. …”