Targeted Delivery of Nitric Oxide by Hemoglobin to Improve Regional Blood Flow in Sickle Cell Disease
Nitric Oxide to Improve Blood Flow in Sickle Cell Disease
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Brief Summary
Nitric oxide is important in regulating blood vessel dilation, and consequently, blood flow.
This gas is continuously produced by cells that line the blood vessels. It is also
transported from the lungs by hemoglobin in red blood cells. This study will examine how this
gas regulates blood vessels and blood flow in people with sickle cell anemia. It will also
look at a possible benefit of using certain genetic information to compare the white blood
cells of people with sickle cell anemia to those without the disease.
Patients with sickle cell anemia and healthy normal volunteers 18 to 65 years of age may be
eligible for this study. Candidates will be screened with a medical history, cardiovascular
physical examination, electrocardiogram and routine blood tests. Participation of volunteers
without sickle cell anemia will be limited to a single blood draw for genetic study. Sickle
cell disease patients will undergo the following procedures:
Patients will lie in a reclining chair during the study. After administration of a local
anesthetic, small tubes will be inserted through a needle into the artery and vein of the
patient's forearm. These are used to measure blood pressure and draw blood samples during the
study. Forearm blood flow will be measured using pressure cuffs placed on the wrist and upper
arm, and a strain gauge (a rubber band device) placed around the forearm. When the cuffs are
inflated, blood flows into the arm, stretching the strain gauge, and the flow measurement is
recorded. A small lamp will be positioned over the hand. Light reflected back from the hand
provides information about nitric oxide and hemoglobin in the blood of the skin. A squeezing
device called a dynamometer will be used to measure handgrip strength.
Baseline blood flow, nitric oxide, hemoglobin, and handgrip will be measured after an
infusion of glucose (sugar) and water. These measurements will be repeated at various times
before, during and after administration of small doses of the following drugs:
- Sodium nitroprusside - causes blood vessels to dilate and increases blood flow to the
heart
- Acetylcholine - causes blood vessels to dilate and slows heart rate
- LNMMA - decreases blood flow by blocking the production of nitric oxide
There will be a 20- to 30-minute rest period between injections of the different drugs.
When the above tests are completed, the patient will breathe a mixture of room air and nitric
oxide for 1 hour through a facemask placed over the face, after which forearm blood flow and
light reflected from the hand will be measured. Then the patient will do the handgrip
exercise for 5 minutes, after which blood flow and hand lamp measurements will be taken.
After a 20-minute rest period (with continued breathing of room air/nitric oxide), L-NMMA
will be infused again. The handgrip exercise, blood flow and hand lamp measurements will be
repeated. The face mask will then be removed, and the tubes will be removed 20 minutes later.
Blood samples will be collected at various times during the 5- to 6-hour study through the
tubes in the arm. Some of the blood will be used to look at genes that make proteins involved
in cell-to-cell communication, inflammation, and in making red and white blood cells stick to
the lining of blood vessels.
Detailed Description
Sickle cell anemia 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. Acute pain crisis and acute chest
syndrome are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been
proposed as a possible therapy for the acute chest syndrome. Anecdotally, NO has been
described to rapidly improve the hypoxemia and the clinical course of the acute chest
syndrome. Furthermore, a number of recent studies have suggested that NO may have a favorable
impact on sickle red cells at the molecular level and could improve the abnormal
microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial is
designed to test the hypotheses that 1) individuals with sickle cell anemia have endothelial
dysfunction with reduced local synthesis and release of NO, that may reduce regional
perfusion at rest and impair the vasodilator response to stress, and 2) during NO inhalation,
delivery of NO bound to hemoglobin will be enhanced and will improve these abnormalities in
regional vascular perfusion. Studies will be performed on untreated sickle cell anemia
patients and on patients managed with chronic hydroxyurea therapy. Demonstration of improved
regional perfusion with NO therapy could have significant implications for patient management
during acute pain crisis and the acute chest syndrome.
Overall Status
Completed
Start Date
2001-01-01
Completion Date
2003-01-01
Primary Completion Date
N/A
Phase
Phase 2
Study Type
Interventional
Enrollment
65
Condition
Intervention
Eligibility
Criteria
INCLUSION CRITERIA
Males or females 18 to 65 years of age are eligible.
Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S beta(0)
thallassemia genotype is required).
Hematocrit greater than 18 percent (with an absolute reticulocyte count greater than
100,000/ml).
Volunteer subjects taking hydroxyurea must have been on therapy with the drug for at least
four months. Volunteer subjects not taking hydroxyurea must have been off of therapy with
the drug for at least 4 months.
EXCLUSION CRITERIA
Clinically unstable sickle cell anemia defined as having an acute pain crisis within the
last week.
Age less than 18 years or greater than 65 years.
Current pregnancy or lactation.
Conditions that may independently affect endothelial function:
1. Diabetes mellitus or Fasting blood sugar greater than 120 mg/dL
2. Cigarette smoking within two years
3. Hypertension (diastolic blood pressure greater than 90 mmHg)
4. Lipid abnormalities (LDL cholesterol greater than 160 mg/dL, HDL cholesterol less than
30 mg/dL, triglycerides greater than 500 mg/dL)
5. Creatinine greater than 1.0 mg/dL
Hematocrit less than or equal to 18 percent: however, patients may return for evaluation at
a later date.
No aspirin or non-steroidal antiinflammatory drugs (NSAIDs for one week and caffeine the
day of the study). Patients on opiates and acetaminophen will not be excluded.
Patients taking sildenafil (Viagra) will be excluded from the study.
Recent transfusion (last 4 weeks) or hemoglobin A greater than 5 percent.
Gender
All
Minimum Age
N/A
Maximum Age
N/A
Healthy Volunteers
Accepts Healthy Volunteers
Location
Facility |
|
Warren G. Magnuson Clinical Center (CC) Bethesda Maryland 20892 United States |
Location Countries
Country
United States
Verification Date
2003-01-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
01-CC-0078
Intervention Browse
Mesh Term
Nitric Oxide
Acetylcholine
Firstreceived Results Date
N/A
Reference
Citation
Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology. 1997 Oct;87(4):988-90.
PMID
9357905
Citation
Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000 Oct 1;96(7):2451-9.
PMID
11001897
Citation
Cardillo C, Kilcoyne CM, Cannon RO 3rd, Panza JA. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension. 1998 Jun;31(6):1235-9.
PMID
9622135
Firstreceived Results Disposition Date
N/A
Study Design Info
Primary Purpose
Treatment
Study First Submitted
February 1, 2001
Study First Submitted Qc
February 1, 2001
Study First Posted
February 2, 2001
Last Update Submitted
March 3, 2008
Last Update Submitted Qc
March 3, 2008
Last Update Posted
March 4, 2008
ClinicalTrials.gov processed this data on August 29, 2018
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.