BackgroundInfusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion.MethodologyHealthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate.Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed.FindingsThe maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood.ConclusionSodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension.Clinical Trial Registration Information http://www.clinicaltrials.gov; NCT00103025

Summary. Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration. Our data showed that chronic HU significantly increased NO, cGMP, and HbF levels in SCD.Recently it was shown that HbF production was stimulated by cGMP-dependent protein kinase. Our results suggest that NO stimulates cGMP production, which then activates a protein kinase and increases the production of HbF.

The mechanism of action of hydroxyurea (HU) in decreasing the frequency of pain crisis in sickle cell disease (SCD) has not been fully elucidated. In vitro and in vivo studies suggest that nitric oxide (NO), a potent vasodilator, may partly be responsible for the beneficial effect of HU. This study was designed to determine the effect of oral administration of HU on plasma levels of NO metabolites (NO(x) ) in sickle cell patients (SCP). The results indicate that during steady-state plasma levels of NO(x) were significantly higher in HU-treated patients compared to non HU-treated patients or normal controls (p <.05). In five inpatients in mild pain plasma levels of NO(x) increased significantly after 2 h of HU administration (p <.05); however, in three inpatients in persistent pain with significantly lower baseline NO(x) there was a minimal NO(x) response to HU at 2 h (p <.01). These observations indicate that HU administration is associated with the production of NO in some SCP, but that further study of the pharmacodynamics of this effect is necessary.

We found that patients with sickle cell disease have subnormal values of cerebral oxygen saturation. Red cell transfusions significantly increased the brain oxygenation in these patients. Cerebral oximetry may be a useful, noninvasive method for assessing the effect of circulating normal red cells in sickle cell patients after transfusions.