Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy

Kazunori Murakami, Chris Privalle, Perenlei Enkhbaatar, Katsumi Shimoda, Frank C. Schmalstieg, Joseph DeAngelo, Steve Lee, Lillian D. Traber, Daniel L. Traber

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Interleukin-2 (IL-2), a cytokine that induces natural killer cells termed lymphokine-activated killer (LAK) cells, is in use as an anticancer agent. During IL-2 therapy, adverse effects, such as vasodilatation and hypotension, are common. Previous studies suggest that these effects are due to nitric oxide (NO). Therefore a model of IL-2-induced hyperdynamic response in sheep was developed to test the effect of pyridoxalated haemoglobin polyoxyethylene conjugate (PHP; a NO scavenger), which is currently in clinical development for the treatment of shock associated with systemic inflammatory response syndrome. Twelve female sheep were divided into four groups (n = 3 per group): sham control (Ringer's lactate solution), PHP alone (20 mg · kg-1 · h-1 for 96 h). IL-2 alone (recombinant human IL-2; I 440 000 units/kg intravenously every 8 h) and a combination of PHP and IL-2. All of the sheep received Ringer's lactate solution to maintain haematocrit at baseline levels. The sheep had free access to food and water. A fall in the mean arterial pressure and systemic vascular resistance index by 20% was observed in the IL-2 group, but not in the PHP+IL-2 group. The fluid requirement to maintain the haematocrit was higher in the IL-2 group (5 ml · kg-1 · h-1) than in the PHP+IL-2 group (4 ml · kg-1 · h-1). The sham group showed no changes in any of the parameters. Scavenging NO by PHP prevented the hyperdynamic reaction induced by IL-2 administration in sheep. This activity of PHP may prevent the early discontinuation of IL-2 therapy that results because of these adverse events.

Original languageEnglish (US)
Pages (from-to)629-635
Number of pages7
JournalClinical Science
Volume105
Issue number5
DOIs
StatePublished - Nov 2003

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Keywords

  • Cytokine therapy
  • Lung oedema
  • Sheep
  • Systemic vascular resistance
  • Vascular leakage

ASJC Scopus subject areas

  • Medicine(all)

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