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

Kent Yip, Vicky Goh, Jane Gregory, Ian Simcock, J. James Stirling, N. Jane Taylor, Robert Kozarski, Andrew Mitchell, Sam Bosopem, Gavin Halbert, Roberto Alonzi, David Miles, Peter Hoskin

Research output: Contribution to journalArticle

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.
LanguageEnglish
Article number05
Pages44-52
Number of pages9
JournalJournal of Cancer Therapy
Volume5
Issue number1
DOIs
Publication statusPublished - 8 Jan 2014

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Nitric Oxide Synthase
Perfusion
Kidney
Pharmaceutical Preparations
Renal Circulation
Neoplasms
Blood Pressure
Cone-Beam Computed Tomography
Blood Volume
Informed Consent
Blood Vessels

Keywords

  • L-NNA
  • nitric oxide
  • perfusion
  • vascular
  • imaging
  • cancer

Cite this

Yip, Kent ; Goh, Vicky ; Gregory, Jane ; Simcock, Ian ; Stirling, J. James ; Taylor, N. Jane ; Kozarski, Robert ; Mitchell, Andrew ; Bosopem, Sam ; Halbert, Gavin ; Alonzi, Roberto ; Miles, David ; Hoskin, Peter. / The acute physiological effects of the vaso-active drug, L-NNA, a nitric oxide synthase inhibitor, on renal and tumour perfusion in human subjects. In: Journal of Cancer Therapy. 2014 ; Vol. 5, No. 1. pp. 44-52.
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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.",
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Yip, K, Goh, V, Gregory, J, Simcock, I, Stirling, JJ, Taylor, NJ, Kozarski, R, Mitchell, A, Bosopem, S, Halbert, G, Alonzi, R, Miles, D & Hoskin, P 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, vol. 5, no. 1, 05, pp. 44-52. https://doi.org/10.4236/jct.2014.51006

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; Goh, Vicky; Gregory, Jane; Simcock, Ian; Stirling, J. James; Taylor, N. Jane; Kozarski, Robert; Mitchell, Andrew; Bosopem, Sam; Halbert, Gavin; Alonzi, Roberto; Miles, David; Hoskin, Peter.

In: Journal of Cancer Therapy, Vol. 5, No. 1, 05, 08.01.2014, p. 44-52.

Research output: Contribution to journalArticle

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T1 - The acute physiological effects of the vaso-active drug, L-NNA, a nitric oxide synthase inhibitor, on renal and tumour perfusion in human subjects

AU - Yip, Kent

AU - Goh, Vicky

AU - Gregory, Jane

AU - Simcock, Ian

AU - Stirling, J. James

AU - Taylor, N. Jane

AU - Kozarski, Robert

AU - Mitchell, Andrew

AU - Bosopem, Sam

AU - Halbert, Gavin

AU - Alonzi, Roberto

AU - Miles, David

AU - Hoskin, Peter

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Y1 - 2014/1/8

N2 - 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.

AB - 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.

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KW - nitric oxide

KW - perfusion

KW - vascular

KW - imaging

KW - cancer

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DO - 10.4236/jct.2014.51006

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