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The efficacy of aprotinin to reduce intraoperative bleeding tendency in cardiac operations has been demonstrated in several studies. Aprotinin is a polybasic polypeptide and has antigenic properties. Anaphylactic reactions to aprotinin have been described. The aim of the present study was to evaluate the prevalence of adverse reactions to reexposure to high-dose aprotinin. The clinical outcome of all patients undergoing heart operations in our institution between 1988 and 1995 with at least two exposures to aprotinin was investigated. There were 248 reexposures to aprotinin in 240 patients: 101 adult and 147 pediatric cases. The total aprotinin doses were 4.9 x 10(6) (interquartile range 2 x 10(6)) KIU (adults) and 1.3 x 10(6) (interquartile range 1.2 x 10(6)) KIU (pediatric patients). The time between the first and second aprotinin exposures was 344 (interquartile range 1039) days. Seven adverse reactions to aprotinin were found (2.8%). The severity of the reaction ranged from mild (no intervention) to severe (longer-lasting circulatory depression despite vasopressor therapy). All patients survived the event. Patients with an interval less than 6 months since the previous exposure had a statistically higher incidence of adverse reactions than patients with a longer interval (5/111 or 4.5% vs 2/137 or 1.5%, p < 0.05). Two patients reacted to a test dose of 10,000 KIU aprotinin. Pretreatment with antihistaminics was done in 60% of the patients. We recommend the following procedure for reexposure with high-dose aprotinin: (1) delay of the first bolus injection of aprotinin until the surgeon is ready to begin cardiopulmonary bypass, (2) test dose of 10,000 KIU aprotinin in all patients with aprotinin treatment, (3) H1/H2 blockade in known or possible reexposures, and (4) avoidance of reexposure within the first 6 months after the previous exposure to aprotinin. With these precautions a reexposure to aprotinin in patients with a high risk of bleeding is justified, because the benefits of aprotinin treatment outweigh the relative risk of a serious allergic reaction.

A novel murine enzyme, ADP-dependent glucokinase (ADPGK), has been shown to catalyse glucose phosphorylation using ADP as phosphoryl donor. The ancestral ADPGK gene appears to have been laterally transferred from Archaea early in metazoan evolution, but its biological role has not been established. Here, we undertake an initial investigation of the functional properties of human ADPGK in human tumour cell lines and specifically test the hypothesis that ADPGK might prime glycolysis using ADP under stress conditions such as hypoxia. Recombinant human ADPGK was confirmed to catalyse ADP-dependent glucose phosphorylation in vitro, with an apparent K (M) for glucose of 0.29 mM. Expression databases and western blotting of surgical samples demonstrated high expression in many human tissues, including tumours. Unlike hexokinase-2 (HK2), RNAi studies with exon arrays showed that ADPGK is not a transcriptional target of hypoxia inducible factor-1. Consistent with this, ADPGK protein was not upregulated by hypoxia or anoxia. Surprisingly, stable fivefold overexpression of ADPGK in H460 or HCT116 cells had no apparent effect on proliferation or glycolysis, and did not rescue clonogenicity or glycolysis when HK2 was suppressed by siRNA. Furthermore, suppression of ADPGK by siRNA did not cause detectable inhibition of glycolysis or cell killing by anoxia, although it did induce a statistically significant decrease in plating efficiency of H460 cells under aerobic conditions. Thus, human ADPGK catalyses ADP-dependent phosphorylation of glucose in vitro, but despite its high expression in human tumour cell lines it appears not to make a quantifiable contribution to glycolysis under the conditions evaluated.