Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00095472
First received: November 4, 2004
Last updated: March 14, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Sickle Cell Anemia
Drug: L-NMMA
Drug: Sodium Nitrite
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

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

Enrollment: 18
Study Start Date: November 2004
Study Completion Date: August 2007
Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: L-NMMA
    N/A
    Drug: Sodium Nitrite
    N/A
Detailed Description:

Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemia-reperfusion injury and infarction. Our published data indicate that up to 50% of sickle cell patients have endothelial dysfunction due to impaired bioavailability of endogenous nitric oxide due in large part to scavenging of nitric oxide by cell-free plasma hemoglobin. These data suggest that therapies directed at restoring NO bioavailability might prove beneficial. We have recently discovered that the nitrite anion, available currently for human use as a component of the cyanide antidote kit, is a vasodilator in vivo by generating nitric oxide (NO) in tissues with lower oxygen tension and pH. The mechanism involves a novel physiological function of human hemoglobin as an oxygen- and pH dependent nitrite reductase. To date we have observed that nitrite infusions in animal models significantly reduce liver and cardiac ischemia-reperfusion injury and infarction in mouse models, prevent cerebral vasospasm after subarachnoid hemorrhage in primates, and decrease pulmonary hypertension in newborn hypoxic sheep. The current protocol is designed as a phase I/II trial to address the hypothesis that nitrite infusions will vasodilate the circulation in patients with sickle cell disease at rest and during vaso-occlusive pain crisis, inactivate circulating cell-free plasma hemoglobin, reduce pulmonary artery pressures and reduce ischemia-reperfusion injury (measured by circulating markers of oxidant stress).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

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

EXCLUSION CRITERIA:

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

Red cell G6PD activity below normal range (All subjects will be tested for red blood cell G6PD deficiency; levels below the lower limits of normal will result in exclusion from participation in the study)

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00095472

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: John F Tisdale, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00095472     History of Changes
Other Study ID Numbers: 050016, 05-H-0016
Study First Received: November 4, 2004
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Blood Flow
Nitric Oxide
Vascular Function
Vasodilation
Vaso-Occlusive Pain Crisis
Sickle Cell Disease

Additional relevant MeSH terms:
Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on July 20, 2014