1. Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy.
- Author
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Murakami K, Privalle C, Enkhbaatar P, Shimoda K, Schmalstieg FC, Deangelo J, Lee S, Traber LD, and Traber DL
- Subjects
- Animals, Dose-Response Relationship, Drug, Female, Hematocrit, Humans, Hypotension immunology, Hypotension metabolism, Interleukin-2 therapeutic use, Lymphocyte Count, Models, Animal, Recombinant Proteins therapeutic use, Sheep, Water-Electrolyte Balance, Hemoglobins therapeutic use, Hypotension etiology, Immunotherapy, Active adverse effects, Interleukin-2 adverse effects, Nitric Oxide antagonists & inhibitors, Polyethylene Glycols therapeutic use
- 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 x kg(-1) x h(-1) for 96 h), IL-2 alone (recombinant human IL-2; 1,440,000 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 x kg(-1) x h(-1)) than in the PHP+IL-2 group (4 ml x kg(-1) x 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.
- Published
- 2003
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