Phase I study of the safety and pharmacologic effects of diaspirin cross-linked hemoglobin solution

Abstract

OBJECTIVE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of diaspirin cross-linked hemoglobin solution (DCLHb) in normal, healthy volunteers. DESIGN: Randomized, double-blind, controlled, crossover study. SETTING: Phase I research facility of a contract research organization. PATIENTS: Twenty-four healthy adult volunteers. INTERVENTIONS: Diaspirin cross-linked hemoglobin solution (25, 50, or 100 mg/kg) or equal volume of lactated Ringer's solution was infused on day 1; the alternate solution was infused 6 days later. Laboratory analyses, electrocardiograms, and Holter and telemetry monitoring were performed to assess organ function, pharmacokinetics, and potential toxicity. Vital signs, pulse oximetry, laser Doppler flowmetry, and toe temperature were measured to evaluate diaspirin cross-linked hemoglobin solution's pharmacodynamic effects. MEASUREMENTS AND MAIN RESULTS: There were no serious adverse events associated with diaspirin cross-linked hemoglobin solution infusion. Abdominal pain occurred in three subjects after control infusion and in six subjects after diaspirin cross-linked hemoglobin solution infusion; no treatment was required. A dose-related increase in lactic dehydrogenase (LDH)-5 isoenzyme concentrations was observed in 12 subjects after diaspirin cross-linked hemoglobin solution infusion. There were no associated increases in the circulating concentrations of total LDH, aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase. Total serum creatine kinase concentrations increased significantly after infusion of 100 mg/kg of diaspirin cross-linked hemoglobin solution; the isoenzyme creatine kinase-myocardial band (CK-MB) was not increased, nor were there any abnormal electrocardiogram findings. There were no differences in laser Doppler, pulse oximetry, or toe temperature measurements during or after either infusion. The half-life of diaspirin cross-linked hemoglobin solution was 2.5 hrs for the 25- and 50-mg/kg doses and 3.3 hrs for the 100-mg/kg dose. A dose-related increase in blood pressure occurred with diaspirin cross-linked hemoglobin solution. CONCLUSIONS: Diaspirin cross-linked hemoglobin solution doses of 25, 50, and 100 mg/kg are well tolerated, without evidence of organ dysfunction or toxicity. Diaspirin cross-linked hemoglobin solution's pressor effect is without evidence of decreased peripheral perfusion. Further investigations of its use in certain patient populations are warranted.