Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease
Maneno muhimu
Kikemikali
Maelezo
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).
Tarehe
Imethibitishwa Mwisho: | 12/06/2015 |
Iliyowasilishwa Kwanza: | 11/03/2004 |
Uandikishaji uliokadiriwa Uliwasilishwa: | 11/03/2004 |
Iliyotumwa Kwanza: | 11/04/2004 |
Sasisho la Mwisho Liliwasilishwa: | 11/01/2019 |
Sasisho la Mwisho Lilichapishwa: | 11/04/2019 |
Tarehe halisi ya kuanza kwa masomo: | 10/31/2004 |
Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 08/23/2007 |
Tarehe ya Kukamilisha Utafiti: | 08/23/2007 |
Hali au ugonjwa
Uingiliaji / matibabu
Drug: L-NMMA
Drug: Sodium Nitrite
Awamu
Vigezo vya Kustahiki
Zama zinazostahiki Kujifunza | 18 Years Kwa 18 Years |
Jinsia Inastahiki Kujifunza | All |
Hupokea Wajitolea wa Afya | Ndio |
Vigezo | - 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 |
Matokeo
Hatua za Matokeo ya Msingi
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. [undefined]