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.


METHODS
Randomized, placebo-controlled, double-blind study.


METHODS
Clinical research facility of a contract research organization.


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


METHODS
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.


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.


CONCLUSIONS
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.
Clinical Affairs Division of Hemosol Inc., Toronto, ON, Canada.
F J
FJ
Carmichael
A C
AC
Ali
J A
JA
Campbell
S F
SF
Langlois
G P
GP
Biro
A R
AR
Willan
C H
CH
Pierce
A G
AG
Greenburg
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D004573:Electrolytes / Q000097:blood; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011887:Raffinose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D004573:Electrolytes; D006454:Hemoglobins; C097124:O-raffinose cross-linked human hemoglobin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011887:Raffinose; D001663:Bilirubin