title: Effects of intravenous ABT-870 (iron (III)-hydroxide oligosaccharide) on mean arterial pressure and heart rate in the anaesthetized beagle: comparison with other iron-containing haematinic agents.
abstract: Iron-deficiency anaemia, a complication of end-stage renal disease (ESRD), is often treated with parenteral iron therapies that have been shown to produce dose-limiting hypotension in patients. ABT-870 (iron-(III)-hydroxide-oligosaccharide) is comprised of elemental iron complexed with oligosaccharide, a composition that we hypothesised would allow the hypotensive effects of parenteral iron therapy to be overcome, thus allowing a rapid rate of infusion to be well tolerated. Mean arterial pressure (MAP) and heart rate (HR) were monitored in anaesthetized dogs following the infusion of ABT-870 and iron sucrose administered at doses of 7.1 and 21.3 mg/kg using a rapid 30 s infusion. ABT-870 and iron sucrose were also monitored at doses of 7.1, 21.3 and 50 mg/kg administered over a 10 min period. Sodium ferric gluconate complex (SFGC) was administered in an identical fashion at doses of 12.5 and 31.2 mg/kg. A 30 s rapid infusion of ABT-870 at doses of 7.1 and 14.3 mg/kg or a 10 min infusion of ABT-870 at doses of 7.1 and 21.3 mg/kg produced little effect on MAP and HR. Infusion of the highest dose of ABT-870 (50 mg/kg) produced no consistent hypotension, but did produce an increase in HR (maximal increase 35 +/- 9 b.p.m.), an effect that lasted only 15 min. A 30 s rapid infusion of iron sucrose at 7.1 mg/kg produced modest increases in MAP and HR (5 +/- 1 mmHg and 5 +/- 2 b.p.m., respectively). However, rapid infusion of iron sucrose at 14.3 mg/kg produced hypotension (to -8 +/- 1 mmHg below baseline) and exerted variable, biphasic effects on HR ranging from -16 to +50 b.p.m. Although 10 min infusion of iron sucrose at 7.1 mg/kg exerted little effect on MAP and HR, at doses of 21.3 and 50 mg/kg iron sucrose elicited a profound dose-dependent decrease in MAP (-34 +/- 11 and -83 +/- 5 mmHg, respectively) and a pronounced increase in HR ranging from 32 to 49 b.p.m. above baseline. A 10 min infusion of SFGC at doses of 12.5 and 31.2 mg/kg produced a dose-dependent decrease in MAP (-28 +/- 18 and -67 +/- 12 mmHg below baseline) and a marked increase in HR (26 +/- 11 and 94 +/- 15 b.p.m. above baseline). In conclusion, unlike iron sucrose and SFGC, high doses of ABT-870 failed to exert consistent hypotensive effects. These data demonstrate that ABT-870 may have a substantial therapeutic window and considerable clinical potential for iron-replacement therapy.
authors.affiliation: Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA.
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Armin
authors.initials: A
authors.lastname: Gerhardt
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Leticia
authors.initials: L
authors.lastname: Delgado-Herrera
authors.forename: Joel Z
authors.initials: JZ
authors.lastname: Melnick
authors.forename: Laura A
authors.initials: LA
authors.lastname: Williams
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003911:Dextrans; D004285:Dogs; D005290:Ferric Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006397:Hematinics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D058085:Iron Compounds / Q000494:pharmacology*; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C508623:ABT-870; D000959:Antihypertensive Agents; D003911:Dextrans; D005290:Ferric Compounds; D006397:Hematinics; D058085:Iron Compounds; D009844:Oligosaccharides; C035552:ferric gluconate