Effect of Blood Clot in the Subarachnoid Space For years different drugs have been administered intrathecally/intraventricularly in an attempt to prevent or reverse this vasospasm, but without clinical success. We hypothesized 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. We examined this hypothesis, in a primate model of subarachnoid hemorrhage injecting dye (for macro-imaging) and contrast (for radiological imaging) into the intrathecal space and evaluating the extent of their distribution to the subarachnoid cisterns. A manuscript summarizing the findings confirming our hypothesis has been submitted. Effect of Nitric Oxide (NO) on Vasospasm For several years 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 also reported that nitrite acts as a local, on-demand NO donor preventing development of vasospasm in a preclinical study in primates. After receiving IRB and FDA approval for a clinical protocol, we have 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. The results of this study have been analyzed and a manuscript has been submitted.
