title: Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy.
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.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch and Shriners Hospital for Children, Galveston, TX 77555, USA. kmurakam@utmb.edu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Chris
authors.initials: C
authors.lastname: Privalle
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shimoda
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schmalstieg
authors.forename: Joseph
authors.initials: J
authors.lastname: Deangelo
authors.forename: Steve
authors.initials: S
authors.lastname: Lee
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D007022:Hypotension / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D016233:Immunotherapy, Active / Q000009:adverse effects*; D007376:Interleukin-2 / Q000009:adverse effects* / Q000627:therapeutic use; D018655:Lymphocyte Count; D023421:Models, Animal; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012756:Sheep; D014882:Water-Electrolyte Balance
chemical_list: D006454:Hemoglobins; D007376:Interleukin-2; D011994:Recombinant Proteins; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D009569:Nitric Oxide; D011092:Polyethylene Glycols