Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease

NCT00095472 | Completed Phase 1

• 2 other identifiers: 05001605-H-0016
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This study examines ways in which nitric oxide (NO), an important molecule that controls how blood flows through the body's vessels, might be restored with a compound called sodium nitrite. It is hoped that the result will reverse the effect of decreased flow of blood due to sickled cells-that is, cells that have changed into the shape of a crescent or sickle. Sickle cell disease is the most common genetic disease affecting African Americans. About 8% of that population has the sickle cell trait. The changed cells can become attached to blood vessels, decreasing blood flow to vital organs. There can be the loss of needed proteins, including hemoglobin, that deliver oxygen throughout the body. Adults at least 18 years of age who have the SS form of sickle cell disease or S-beta-thalassemia, are in either a steady state or crisis, give informed and written consent for participation, and have had a negative pregnancy test may be eligible for this study. Adults with any other disease that puts them at risk for reduced circulation are not eligible. Women who are breastfeeding are not eligible. Participants will undergo a medical history, including family medical history, and a detailed physical evaluation, to take about 1 hour. There will be a collection of blood; echocardiogram, which involves taking a picture of the heart and its four chambers; and measurement of exhaled carbon monoxide, carbon dioxide, and NO. A procedure called orthogonal polarization spectral imaging will be performed. A small object the size of a Popsicle stick will be placed under the tongue or on a fingertip. This procedure presents a picture of blood flow and how the red blood cells appear as they circulate through blood vessels. The study will be conducted in the Vascular Laboratory/Cardiovascular Floor or Intensive Care and will last about 4 hours. During the study, patients will lie in an adjustable reclining bed and chair. Small tubes will be placed in the artery and vein of the forearm at the inside of the elbow. A small pressure cuff will be applied to the wrist and a larger one to the upper arm. Both cuffs will be inflated with air. A strain gauge, resembling a rubber band, will go around the widest part of the forearm. When the pressure cuffs fill with air, blood will flow into the arm, and information from the strain gauge will be recorded. Between administrations of each medicine, there will be 30-minute rests. Normal saline will be put into the small tube in the artery. Measurements of the blood flow in the forearm will be taken, and a small blood sample will be taken to measure blood counts, proteins, and other natural body chemicals. Then a medicine called sodium nitroprusside, which causes blood vessels to expand and increase blood flow, will be placed into the forearm. It will be given at three different doses for 3 minutes each, with measurements recorded after each dose. Then a medicine called L-NMMA will be placed into the forearm. L-NMMA generally decreases local blood flow by preventing nitric oxide from being produced in the cells lining the blood vessels. It will be given at two different doses for 5 minutes each, with blood flow measured after each dose. Next, nitrite will be placed in the forearm at three different doses for 5 minutes each. Before and after nitrite is given, the researchers will measure the amount of the NO, carbon monoxide, and carbon dioxide that the patients breathe out. Then the procedure for administering normal saline, sodium nitroprusside, and L-NMMA will be repeated, as will a blood test. This study will not have a direct benefit for participants. However, it is hoped that the information gained from the study will help to develop treatment options for patients with sickle cell disease.

Conditions

Sickle Cell Anemia

Keywords

Blood Flow; Nitric Oxide; Vascular Function; Vasodilation; Vaso-Occlusive Pain Crisis; Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• Determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent regional blood flow in patients with sickle cell disease.

Interventions

L-NMMA DRUG

Sodium Nitrite DRUG

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be at least 18 years of age
• Homozygous sickle cell disease or S beta-0-thalassemia/alpha-thalassemia
• Provides informed, written consent for participation

You may not qualify if:

• Patients with currently uncontrolled hypertension (diastolic blood pressures greater than 95 mmHg)
• Hypercholesterolemia (LDL cholesterol greater than 130 mg/dL)
• Diabetes mellitus (fasting blood glucose greater than 120 mg/dL)
• Smoking within one month
• Dietary ingestions of herbal medications, alcohol or caffeine within 12 hours of the study
• Arteriosclerotic cardiovascular disease
• Peripheral arteriosclerotic vascular disease
• Treatment within the last 14 days with sildenafil, vardenafil, tadalafil, inhaled nitric oxide, nitroglycerin or other NO-dependent drugs, such as arginine
• Cytochrome B5 deficiency
• History of reaction to a medication or other substance characterized by dyspnea and cyanosis
• Lactating females (Lactating females will not participate since nitrites cross into breast milk and could cause methemoglobinemia in the infant)
• Pregnancy testing (urine or blood) will be required of all women of reproductive age to exclude current pregnancy

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.

  PMID: 6253831 BACKGROUND

• Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987 Dec;61(6):866-79. doi: 10.1161/01.res.61.6.866.

  PMID: 2890446 BACKGROUND

• Rees DD, Palmer RM, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418-24. doi: 10.1111/j.1476-5381.1989.tb11833.x.

  PMID: 2924084 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Aneurysm

Interventions

omega-N-Methylarginine; Sodium Nitrite

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Nitrites; Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• John F Tisdale, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: November 4, 2004
• First Posted: November 5, 2004
• Study Start: November 1, 2004
• Primary Completion: August 24, 2007
• Study Completion: August 24, 2007
• Last Updated: November 5, 2019

Record last verified: 2015-12-07

Locations

US (1)