A phase I study of oxidized raffinose cross-linked human hemoglobin.

OBJECTIVE

To evaluate the safety of oxidized-raffinose cross-linked human hemoglobin, Hemolink, in normal healthy volunteers.

DESIGN

Randomized, placebo-controlled, double-blind study.

SETTING

Clinical research facility of a contract research organization.

PATIENTS

Forty-two healthy adult male volunteers of which 33 received Hemolink.

INTERVENTIONS

Oxidized-raffinose cross-linked and polymerized hemoglobin as a 10% (w/v) solution, in doses of 0.025-0.6 g/kg or an equivalent volume of lactated Ringer's solution, was infused intravenously on day 1, and subjects were monitored for 3 days in the clinical facility with < or =6 wks follow-up. Major organ function was assessed pre- and postinfusion, by hemodynamic, electrocardiographic, pulmonary function, and clinical chemistry measurements.

MEASUREMENTS AND MAIN RESULTS

Doses of 1.7-42 g of hemoglobin were administered with no serious adverse events noted. Abdominal pain of moderate to severe intensity was seen in some subjects at doses >0.4 g/kg and was alleviated with smooth muscle relaxants. There was a dose-dependent increase in mean arterial pressure with a plateau of approximately 14% above baseline at 0.1 g/kg. There was a concomitant reduction in heart rate, with no electrocardiographic abnormalities found. Respiratory function was not affected. There was a dose-dependent increase in serum bilirubin with values above the upper limit of normal at doses of > or =0.4 g/kg. Small increases in aspartate aminotransferase and alanine aminotransferase were noted in some patients, whereas alkaline phosphatase and gamma-glutamyltransferase remained in the normal range. Serum amylase concentrations were normal in 31 of 33 patients receiving Hemolink, whereas lipase was within the normal range in 21 of 33 patients. LDH was increased in a dose-dependent fashion. Two patients had increased creatine kinase concentrations, with a normal creatine kinase-MB mass fraction. All hematologic variables were within the normal range. The half-life of the oligomeric (>64 kDa) fraction of Hemolink was 18-20 hrs.

CONCLUSION

Oxidized-raffinose cross-linked hemoglobin, Hemolink, at doses < or =0.6 g/kg were well tolerated in healthy volunteers with no evidence of organ dysfunction. Further investigation of its potential use in surgical and trauma settings appears warranted.