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. We have also observed that nitrite induces regional vasodialtion in healthy human subjects. The current protocol was designed as a phase I/II trial to address the hypothesis that nitrite infusions would 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). We began enrolling patients in January 2005. Forearm blood flow studies were completed on fourteen patients. These patients were infused with SNP, L-NMMA and Nitrite at the three designated doses, and there were no significant side effects. The average increase in forearm blood flow over baseline with the SNP doses of 0.8mg/min, 1.6mg/min, and 3.2mg/min were +27%, +12%, and +32% respectively. The average drop in forearm blood flow after the L-NMMA infusions of 4mmol/min and 8mmol/min were -17% and -20% respectively. As hypothesized the forearm blood flow did increase after each successive dose of nitrite. The average increase in forearm flow after the 0.4mM, 4mM and 40mM infusions was +8%, +25%, and +77% respectively. The post nitrite SNP forearm blood flow responses were as predicted, greater than the pre-nitrite forearm flows. There was no statistically significant difference in the pre-nitrite SNP forearm blood flow response and the post-nitrite SNP forearm blood flow response in our 14 patients with sickle cell disease who participated in the study. We have completed the study in subjects in steady state and have submitted our results for publication. At this time we do not intend to pursue part B of the study that was to be performed in subjects during vaso-occlusive crisis. The study is closed to accrual and is open for data and sample analysis only. We are seeking to determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent regional blood flow in patients with sickle cell disease (SS). Forearm blood flow measured at baseline is being compared to the paired forearm blood flow after 40 μM nitrite infusion in each patient (paired students t-test). A significant result will be indicated by an increase in forearm blood flow following nitrite infusion vs. baseline values, with p<0.05. We have completed the study in subjects in steady state. At this time we do not intend to pursue part B of the study that was to be performed in subjects during vaso-occlusive crisis.
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| Mack, A Kyle; McGowan Ii, Vicki R; Tremonti, Carole K et al. (2008) Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study. Br J Haematol 142:971-8 |
