Atorvastatin Therapy to Improve Endothelial Function in Sickle Cell Disease

NCT00072826 | Completed Phase 1

• 2 other identifiers: 04003204-CC-0032
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine the effects of oral atorvastatin on the linings of blood vessels in patients with sickle cell disease, plus the agent's effect on blood markers of inflammation and blood vessel function. Sickle cell disease is a recessive genetic disorder and the most common genetic disease affecting African Americans. Inherited are abnormal genes that make hemoglobin, the substance within red blood cells that carries oxygen from the lungs to the body. In the disease, sickle hemoglobin leads to rigidity or hardness of the red cells, causing obstruction in small blood vessels, inflammation, and injury to organs when the flow of blood to them is blocked. Some medications already prescribed for other diseases, such as atorvastatin, which is used for lowering cholesterol levels, can improve blood flow. Patients 18 to 65 years of age who have sickle cell disease, who have not had an acute pain episode within the previous week, and who are not pregnant or lactating may be eligible for this study. They will undergo a complete medical history; physical examination; baseline blood tests; and echocardiogram, in which an ultrasound wand is placed against the chest wall to get images inside the heart and blood vessels. In addition, patients will have blood flow studies. During the procedure, they will lie in an adjustable reclining chair for 5 to 6 hours. There will be 20- to 30-minute rests between specific activities and blood samples will be drawn intermittently for testing. Small tubes will be placed in the artery of the forearm at the inside of the elbow. Normal saline will be infused into one tube. A small pressure cuff will be applied to the wrist and a larger cuff to the upper arm. Both cuffs will be attached to an inflation device. A device like a rubber band, a strain gauge, will be placed around the widest part of the forearm. When the pressure cuffs are inflated, blood will flow into the arm, stretching the gauge proportion to blood flow, and information will be recorded. Then light reflected from the patients' hand and the blood flow in the forearm will be measured. Activity of the genes in the white blood cells will be measured as well. Small amounts of sodium nitroprusside, widely used to reduce blood pressure in people with dangerously high blood pressure, will be injected and blood flow will be measured. Later, small amounts of acetylcholine will be injected. It usually causes blood vessels to expand. After that, small amounts of L-NMMA will be injected. It usually decreases local blood flow by blocking the production of nitric oxide in the cells lining the arm's blood vessels. Then acetylcholine combined with L-NMMA will be injected. After that, oxypurinol, an agent taken by many patients to prevent gout, will be injected. The procedures will be repeated, with oxypurinol given along with each of the agents, and the measurement of blood flow in the forearm will be measured after each drug combination. Afterward, patients will be treated for 4 weeks at home with oral atorvastatin. They will be asked to visit the Clinical Center every 2 weeks for collection of blood samples and an examination. After 4 weeks of taking atorvastatin orally, they will be asked to return to repeat the blood flow studies, but only the first half will be conducted. The part using oxypurinol will not be needed. Regarding some of the blood samples collected during the study, there will be an examination of the genes found in the white blood cells. Specific attention will go to those genes that make proteins for cell-to-cell interaction and inflammation, plus those that cause blood cells to stick to the lining of blood vessels.

Conditions

Sickle Cell Disease

Keywords

3-hydroxy-3-methlglutaryl (HMG); Inhibitors; Endothelial Function; Leukocyte Gene Expression; Statins; Atorvastatin; Sickle Cell Disease

Interventions

Oxypurinol DRUG

L-NMMA DRUG

Acetylcholine DRUG

Eligibility Criteria

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

You may not qualify if:

• For each enrolled study patient with sickle cell disease, we will recruit an African-American healthy control subject of the same gender, within 3 years of age older or younger than the matched patient.
• Males or females 18 to 65 years of age.
• Diagnosis of sickle cell disease (electrophoretic or HPLC documentation of hemoglobin S only phenotype is required).
• Hemoglobin must be 6-9 g/dL with an absolute reticulocyte count greater than 95,000/microL, or hemoglobin greater than 9 g/dL with no requirement for reticulocyte count.
• Plasma soluble VCAM level above median value for sickle cell patients defined by assays performed in our laboratory on the blood of sickle cell patients seen in our program or tricuspid regurgitant jet velocity (determined by Doppler echocardiography) greater than 2.4 m/sec or has had a subnormal response to L-NMMA or sodium nitroprusside infusion on a previous forearm blood flow study.
• Clinically unstable sickle cell disease defined as having an acute pain crisis within the last week.
• Current pregnancy or lactation.
• Conditions that may independently affect endothelial function:
• Diabetes mellitus or fasting blood sugar greater than 120 mg/dL
• Cigarette smoking within one month
• Hypertension (diastolic blood pressure greater than 90 mmHg)
• Serum creatinine greater than 1.5 mg/dL
• Hemoglobin less than or equal to 6 g/dL; however, patients may return for evaluation at a later date.
• Recent transfusion (last 4 weeks).
• No aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for one week and no caffeine the day of the study. Patients on opiates or acetaminophen will not be excluded.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Quyyumi AA, Dakak N, Andrews NP, Husain S, Arora S, Gilligan DM, Panza JA, Cannon RO 3rd. Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis. J Clin Invest. 1995 Apr;95(4):1747-55. doi: 10.1172/JCI117852.

  PMID: 7706483 BACKGROUND

• Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993 May;87(5):1468-74. doi: 10.1161/01.cir.87.5.1468.

  PMID: 8491001 BACKGROUND

• Britten MB, Zeiher AM, Schachinger V. Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. J Intern Med. 1999 Apr;245(4):315-27. doi: 10.1046/j.1365-2796.1999.00449.x.

  PMID: 10356593 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Oxypurinol; omega-N-Methylarginine; Acetylcholine

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

Intervention Hierarchy (Ancestors)

Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Biogenic Amines; Amines; Organic Chemicals

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 10, 2003
• First Posted: November 11, 2003
• Study Start: November 4, 2003
• Primary Completion: August 24, 2007
• Study Completion: August 24, 2007
• Last Updated: December 12, 2019

Record last verified: 2015-12-07

Locations

US (1)