The acute physiological effects of the vaso-active drug, L-NNA, a nitric oxide synthase inhibitor, on renal and tumour perfusion in human subjects

Yip, Kent and Goh, Vicky and Gregory, Jane and Simcock, Ian and Stirling, J. James and Taylor, N. Jane and Kozarski, Robert and Mitchell, Andrew and Bosopem, Sam and Halbert, Gavin and Alonzi, Roberto and Miles, David and Hoskin, Peter (2014) The acute physiological effects of the vaso-active drug, L-NNA, a nitric oxide synthase inhibitor, on renal and tumour perfusion in human subjects. Journal of Cancer Therapy, 5 (1). pp. 44-52. 05. ISSN 2151-1942

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    Abstract

    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 selec-tive inhibitor of nitric oxide synthase, L-NNA. 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. L-NNA was well tolerated by the four patients who received it. Blood flow (BF) and blood vo-lume (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 tu-mour 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. 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.