The Acute Physiological Effects of the Vaso-Active Drug, L-NNA, a Nitric Oxide Synthase Inhibitor, on Renal and Tumour Perfusion in Human Subjects

Abstract

Purpose: To assess the baseline variation in global renal and tumour blood flow, blood volume and extraction fraction, and changes in these parameters related to the acute physiological effects of a single dose of a non selective inhibitor of nitric oxide synthase, L-NNA. Materials & Methods: Ethical approval and informed consent were obtained for this Phase I clinical study. Patients with advanced solid tumours refractory to conventional therapy were recruited and given L-NNA intravenously at two different dose levels. Volumetric perfusion CT scans were carried out at 1, 24, 48 & 72 hours post L-NNA. Blood pressures were taken at regular interval for 6 hours after LNNA. Results: L-NNA was well tolerated by the four patients who received it. Blood flow (BF) and blood volume (BV) in both tumour and kidney were reduced post L-NNA administration (renal BF—20%; renal BV—19.7%; tumour BF—16.9%; tumour BV—18.6%), though the effect was more sustained in tumour vasculature. A negative correlation was found between the change in systemic blood pressure and vascular supply to the tumour within 1 hour following L-NNA (p < 0.0001). Differences in response to L-NNA by separate target lesions in the same patient were observed. Conclusion: The differential effect of L-NNA on tumour and renal blood flow, and the absence of any significant toxicity in this small cohort of patients permit further dose escalation of L-NNA in future early phase trials. The predictive value of blood pressure change in relation to the acute effect of L-NNA on tumour vasculature deserves further evaluation.