Nitric Oxide Flux and Ureagenesis in Argininosuccinate Synthetase Deficiency (ASSD)(Citrullinemia I)

NCT01610089 | Completed DMC

• 1 other identifier: H-27226
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The urea cycle consists of a series of chemical reactions through which the body converts toxic waste- nitrogen into a substance called urea that can be disposed of easily. While disposal of nitrogen is the major function of the urea cycle, recent research has shown that some enzymes of the urea cycle are also important for the production of nitric oxide. Nitric oxide is an important chemical that has many functions in the human body including regulation of blood pressure. Through this study, the investigators will study the production of nitric oxide in subjects with citrullinemia type 1 by administering stable isotopes to these subjects. Stable isotopes are harmless compounds that can be used to track and measure the production of specific compounds in the human body. The overall goal of this study is to understand if citrullinemia patients have a deficiency of nitric oxide production. This knowledge may have an impact on the treatment of patients with citrullinemia.

Conditions

Citrullinemia

Keywords

citrullinemia; argininosuccinate synthetase deficiency; nitric oxide; urea

Outcome Measures

Primary Outcomes (1)

• Flux of citrulline and nitrate through the urea cycle pathway will be measured in conjunction with an independent measure of total plasma arginine flux.

  Endpoint data to be collected include measurement of isotopic enrichments drawn at 0, 6, 7 and 7.5 hours of infusion. Measurements will include urea, carbon-arginine, guanido-arginine, citrulline, nitric oxide, nitrate and 15N-nitrate.

  0, 6, 7 and 7.5 hours of infusion

Secondary Outcomes (1)

• Total body urea production will be measured by the isotopic dilution of constantly infused [18O][13C]urea.

  0, 6, 7 and 7.5 hours of infusion

Study Arms (1)

stable isotope infusion

EXPERIMENTAL

Infusion of isotopes \[15N2-ureido\] arginine, \[5-13C,4, 4, 5, 5-D4\] citrulline, \[15N\]citrulline, 15N sodium nitrate and \[15N\]\[18O3\] potassium nitrate,\[18O\]\[13C\]urea.

Other: stable isotope infusion

Interventions

stable isotope infusion OTHER

Control subjects: \[15N2-ureido\] arginine (0.69 mg/kg); \[5-13C,4,4,5,5-D4\] citrulline (0.18mg/kg); 15N citrulline (0.03mg/kg); 15N sodium nitrate (0.003 mg/kg), \[15N\]\[18O3\] potassium nitrate (0.03 mg/kg) and \[18O\]\[13C\]urea (1 mg/kg)over 10 minutes. Followed by a 8-hour infusion of \[15N2-ureido\] arginine (0.69 mg/kg/hr); \[5-13C,4,4,5,5-D4\] citrulline (0.18mg/kg/hr), \[15N\]\[18O3\] potassium nitrate (0.003 mg/kg/hr) and \[18O\]\[13C\]urea (0.1 mg/kg/hr). Citrullinemia type 1 subjects,\[15N2-ureido\] arginine (4.14 mg/kg); \[5-13C,4,4,5,5-D4\] citrulline (1.08 mg/kg); 15N citrulline (0.18mg/kg); 15N sodium nitrate (0.003 mg/kg), \[15N\]\[18O3\] potassium nitrate (0.03 mg/kg) and \[18O\]\[13C\]urea (1 mg/kg)over 10 minutes, followed by a 8-hour infusion of \[15N2-ureido\] arginine (4.14 mg/kg/hr); \[5-13C,4,4,5,5-D4\] citrulline (1.08 mg/kg/hr), \[15N\]\[18O3\] potassium nitrate (0.003 mg/kg/hr) and \[18O\]\[13C\]urea (0.1 mg/kg/hr).

Also known as: stable isotopes

stable isotope infusion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be adults (18 years and older) with confirmed diagnosis of Argininosuccinate Synthetase Deficiency (ASSD) (Citrullinemia I) who are able to perform study procedures.
• Diagnosis of citrullinemia I must be confirmed by a \>10 fold elevation of citrulline in plasma and/or decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue and/or identification of pathogenic mutation in the AS gene.
• Subject must be able to take oral or G-tube medication and have a history of adequate compliance of diet and treatment.
• If a woman of child bearing potential and sexually active, participant agrees to use an acceptable method of birth control.
• Most recent serum creatinine level must be less than or equal to 1.5 mg/dl. Serum creatinine measurement may be performed at the subject's local laboratory, but must have been obtained within one year of enrollment.
• Participant agrees to travel to Baylor College of Medicine for the study.
• Control subjects must be over eighteen years of age with no chronic or acute health issues.

You may not qualify if:

• Pregnancy, current acute illness and current hyperammonemic episode.

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (1)

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Links

• Baylor College of Medicine Website

MeSH Terms

Conditions

Citrullinemia

Condition Hierarchy (Ancestors)

Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Brendan Lee, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Molecular and Human Genetics

Study Record Dates

• First Submitted: May 30, 2012
• First Posted: June 1, 2012
• Study Start: December 1, 2012
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: March 20, 2015

Record last verified: 2015-03

Locations

US (1)