Effect of Blood Clot in the Subarachnoid Space For years different drugs have been administered intraventricullary or intrathecally to prevent or reverse vasospasm without clinical success. We have demonstrated that the presence of blood clot in the subarachnoid space prevents drugs from penetrating into the vicinity of the affected cerebral arteries, limiting or precluding a significant vasoactive drug effect from intraventricular or intrathecal delivered drugs. Effect of Nitric Oxide (NO) on Vasospasm We have investigated the mechanism of delayed vasospasm and demonstrated the presence of local NO deficiency from dysfunction of NO synthases within the endothelium and adventitia in a primate model of vasospasm, which was corrected by intracarotid delivery of an NO donor. We demonstrated that nitrite acts as a local, on-demand NO donor preventing development of vasospasm and, more recently, reversing delayed vasospasm in a preclinical study in primates. We assessed the safety in 12 healthy subjects of a 48-hour continuous intravenous infusion of nitrite establishing a maximal tolerated dose and dose limiting toxicity. We found that intravenous infusion of nitrite can be delivered safely and at therapeutic doses in normal subjects. This has lead to a clinical trial using intravenous infusion of nitrite in subarachnoid hemorrhage patients.
