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Physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier in humans.

Abstract：

OBJECTIVE:To evaluate the physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier of bovine origin. DESIGN:Randomized, single-blind, placebo-controlled, dose-escalation study. SETTING:The Upjohn Research Clinics (Kalamazoo, MI). SUBJECTS:Normal healthy adult men between the ages of 18 and 45 yrs. There were 18 subjects who received active treatment and 23 controls. INTERVENTIONS:All subjects had phlebotomy of 15% of blood volume (performed in <15 mins) followed by isovolemic hemodilution (3:1, Ringer's lactate to the volume of whole blood removed) over a 90-min period, and either active drug (polymerized bovine hemoglobin) or a control infusion of lactated Ringer's solution (each infusion given over a total of 4.3 hrs). The subjects randomized to active treatment received a loading dose and a continuous infusion of polymerized bovine hemoglobin for a total dose of 16.5, 24.1, 30.2, 38.0, or 45.0 g. All subjects had an indwelling radial artery catheter (for blood pressure and arterial blood gas measurements), determination of cardiac function (by impedance plethysmography), serial pulmonary function tests (spirometry and diffusion capacity), and metabolic cart measurements. MEASUREMENTS AND MAIN RESULTS:Pharmacokinetics of the plasma bovine hemoglobin demonstrated that the elimination of the hemoglobin-based oxygen carrier was a linear, first-order process and that there was no renal excretion. Peak plasma concentrations were between 1 to 2 g/dL and plasma half-life approached 20 hrs at the highest doses given. Diffusion capacity of oxygen was increased up to 20% above baseline in the 38.0 and 45.0 g groups in comparison with controls (approximately 14% below baseline) between 2 and 24 hrs after the infusion (p < .01). Other pulmonary function tests and arterial blood gas measurements were unremarkable. Arterial oxygen content and oxygen delivery tended to be greater in active groups than in controls. CONCLUSIONS:The plasma concentrations of bovine hemoglobin were directly proportional to the doses administered. An increase in diffusion capacity paralleled the plasma bovine hemoglobin concentrations. Dosing of the hemoglobin-based oxygen carrier of bovine origin to a target plasma hemoglobin concentration can be achieved using pharmacokinetic principles with measurable effects on oxygen physiology.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Hughes GS Jr,Antal EJ,Locker PK,Francom SF,Adams WJ,Jacobs EE Jr

doi

10.1097/00003246-199605000-00006

subject

Has Abstract

pub_date

1996-05-01 00:00:00

pages

756-64

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier in humans.