Hemodynamic effects of intraatrial administration of deferoxamine or deferoxamine-pentafraction conjugate to conscious dogs.
Deferoxamine (DFX) is a specific Fe3+ chelator that is used to manage iron overload, and is being evaluated as an agent to reduce ischemic organ damage that involves iron-mediated OH formation. However, high intravascular doses cause significant hemodynamic changes that may limit or counteract beneficial effects. We used conscious, closed-chest dogs to test the hypothesis that conjugating DFX to pentafraction, a high molecular weight fraction of pentastarch, could reduce such hemodynamic changes. We infused 50 mg/kg of body weight of native DFX, or an equivalent dose as DFX-pentafraction, intraatrially over 15 min. Within 10 min of starting the infusion. DFX increased heart rate from pre-drug values of 105 +/- 11 (mean +/- SEM; N = 9) to 158 +/- 13 beats/min, and reduced left ventricular (LV) systolic pressure from 131 +/- 3 to 99 +/- 16 mm Hg, LV end-diastolic pressure from 12 +/- 3 to 3 +/- 3 mm Hg, and mean arterial pressure (MABP) from 101 +/- 5 to 74 +/- 13 mm Hg. In two dogs, MABP decreased to less than or equal to 35 mm Hg. These parameters returned to predrug values by 60 min after infusion. All of these changes were statistically significant (p less than 0.05). In contrast, infusing DFX-pentafraction (N = 9) caused no significant cardiac or hemodynamic changes other than a transient and slight (approximately 7%) increase in systolic arterial pressures. This conjugate, which prolongs the plasma half-life and does not alter the iron-chelating activity of native DFX, eliminates many undesirable hemodynamic actions. It may be a useful therapeutic alternative to native DFX in some settings.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
J R
JR
Forder
T B
TB
McClanahan
K P
KP
Gallagher
B E
BE
Hedlund
P E
PE
Hallaway
M
M
Shlafer
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003676:Deferoxamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007261:Infusions, Intra-Arterial; D007958:Leukocyte Count / Q000187:drug effects; D008970:Molecular Weight; D016276:Ventricular Function
D006895:Hydroxyethyl Starch Derivatives; D003676:Deferoxamine