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The urea cycle is a series of chemical reactions through which the body converts the toxic waste nitrogen into a substance called urea that can be disposed of by the body 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 producing nitric oxide. Nitric oxide is an important chemical with many functions in the body including regulating blood pressure. Through this study, researchers will study the production of nitric oxide in people with citrullinemia type 1 using stable isotopes. Stable isotopes are harmless compounds that can be used to track and measure the production of specific chemicals in the body. The goal of this study is to understand if people with citrullinemia have problems producing nitric oxide. Understanding this may improve the treatment for patients with citrullinemia.
Much of the body’s organs and muscles are made up of protein. The building blocks of protein are amino acids. To keep healthy, the body is always making new protein and breaking down old protein that has become damaged or old. It must also break down the protein we eat into a form it can use.
When protein is broken down, a substance called nitrogen is formed. Normally the body deals with this nitrogen by combining it with other things to make a harmless substance called urea through a process called the urea cycle. People with urea cycle disorders are not able to make as much of this urea from nitrogen. Because of this, they can have too much nitrogen (in the form of ammonia) in their blood. This build-up of ammonia can harm them.
In this study, researchers will be working with people who have been diagnosed with argininosuccinate synthetase deficiency (ASSD) (citrullinemia), a disease belonging to the family of urea cycle disorders. When first diagnosed, people with citrullinemia usually have high levels of two substances in their blood-ammonia and citrulline. This is because the chemical needed to clear these substances from the blood stream is not produced.
In a study completed in August of 2009, stable isotopes were used to measure how well participants' bodies were able to change nitrogen to urea. Stable isotopes are very small particles already in us in small amounts. The structure of isotopes is slightly different from other molecules, so by giving a small amount through an infusion into a vein, we are able follow them as they go through the urea cycle. The production of nitric oxide, an important chemical thought to be involved in how veins and arteries work, was also measured in participants. The results of that study suggest that the urea cycle does not produce much of the body's total nitric oxide. But to confirm this, more studies are needed. Because citrullinemia involves a particular defect in the urea cycle, we will be able to study this finding further and better measure how much of the body's nitric oxide comes from the urea cycle.
The research questions are:
- How much citrulline and nitrate moves through the urea cycle pathway at 0, 6, 7 and 7½ hours of isotope infusion (receiving isotopes directly into a vein (by IV))?
- How much urea is produced in the body at 0, 6, 7 and 7½ hours of isotope infusion?
About this Study
You will be one of approximately 3 subjects with citrullinemia to be asked to participate in this study. Members of your family who also have citrullinemia may participate. In addition, three control subjects without urea cycle disorders will be studied in order to compare your results to theirs.
Your consent to participate in the study may be obtained in person or over the telephone. Study staff will go over the study with you and answer any questions you may have.
The research will be performed during a 4-day inpatient stay at the Baylor College of Medicine General Clinical Research Center in Houston, Texas. You may be admitted at 7AM on the morning of the first day of study or the evening before. Upon admission, a doctor will perform a physical examination and ask you questions about your medical history. During the physical examination, the doctor will listen to your chest and abdomen with a stethoscope, test your reflexes and look in your nose, mouth, and ears. In addition, the doctor will examine your arms and legs, skin, muscles, joints, and spine and test your ability to walk and move. Your vital signs, including heart rate, blood pressure, rate of breathing and body temperature will be measured, and your height and weight will be taken. A urine pregnancy test will be performed on all women able to have children.
On the night before your first day, you will be asked to not eat or drink anything after midnight. (This is called an overnight fast).
Day 1: We will draw 8 mL (about one and a half teaspoons) of blood in the morning. From this sample we will measure how many red and white blood cells you have. This is to rule out anemia (too few red blood cells) or infection (often causes a high number of white cells). The chemistry of your blood will also be measured. This is to be sure that the levels of certain substances like sodium and potassium are normal, that your blood sugar is not too high or too low, and that your liver and kidneys are working well. The blood will also be sent to the lab to test your ammonia level (the by-product of protein breakdown) and amino acids (the building blocks of protein).
While you are staying at the research center, you will be placed on a protein-restricted diet or your usual metabolic diet. Study staff will monitor and measure everything you eat and drink throughout your stay.
Day 2: You will continue on the protein-restricted diet or your usual metabolic diet. At midnight, you will begin another overnight fast to prepare for the Day 3 specimen collections.
Day 3: In the morning, we will put two small tubes (catheters) into veins on your hands or arms. These catheters will be taped to your hands or arms and remain there for the next 8-9 hours. When the first catheter is placed, we will draw 8 ml (about 1 ½ teaspoons) of blood. From this sample we will measure your blood ammonia, plasma amino acids and stable isotopes levels. Once both catheters are in place, we will give you small doses of stable isotopes arginine, citrulline, sodium nitrate and potassium nitrate and urea through your vein over 10 minutes followed by an 8-hour infusion of arginine, citrulline, potassium nitrate and urea. 30 minutes after the start of the infusion, we will draw more blood (for potassium specific blood chemistry) through the catheter not being used for the infusion. Additional blood will be drawn at 6, 7 and 7 ½ hours after the start of the infusion to measure the levels of isotopes in your blood. With the last blood sampling at 7½ hours, your blood ammonia and plasma amino acid levels will also be checked. A total of 35 mL (7 teaspoons) of blood will be taken during day 3, and a total of 43 mL (just under 9 teaspoons) will be drawn during the entire study.
All your urine will be collected over a 24 hour-period. Your participation in the study ends when you are discharged on day 4 after the urine collection is completed.
All procedures conducted during this study are being performed for research purposes. You can see and get a copy of your research related health information. Your research doctor may be able to provide you with part of your information while the study is in progress and the rest of your information at the end of the study. If you provided us with your contact information, you will be given the results of the whole study when it is completed. These results will be explained to you in way you can understand.
To be eligible to participate, you must:
- Be an adult (18 years and older) with the diagnosis of Argininosuccinate Synthetase Deficiency (ASSD) (Citrullinemia I) ((as confirmed by lab test or genetic test).
- Be able to take medicine orally or through a gastric-tube.
- Comply with diet and treatment.
- Have a recent blood serum creatinine level less than or equal to 1.5 mg/dl. Serum creatinine measurement may be performed at the the participant's local laboratory, but must have been obtained within one year before enrolling in the study.
- Be able to perform study procedures.
- Agree to travel to Baylor College of Medicine (in Houston, Texas) for the study.
You are not eligible to participate if:
- Are pregnant or breastfeeding.
- Have a current acute illness or hyperammonemic episode.