title: Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia.
abstract: The anticancer agent 3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase's small subunits, M2 and M2b (p53R2). Unfortunately, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe(2+)) in hemoglobin. This creates Fe(3+) methemoglobin that does not deliver oxygen. Fe(2+) in hemoglobin normally auto-oxidizes to inactive Fe(3+) methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen, ascorbate and, most importantly, intravenously administered methylene blue as a therapeutic antidote.
authors.affiliation: Department of Epidemiology & Biostatistics, University Hospitals Case Medical Center & Case Western Reserve School of Medicine, Cleveland, OH 44106, USA. charles.kunos@UHhospitals.org
authors.forename: Charles A
authors.initials: CA
authors.lastname: Kunos
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ingalls
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
mesh_terms: D000931:Antidotes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008706:Methemoglobin / Q000378:metabolism; D008708:Methemoglobinemia / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D008751:Methylene Blue / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000931:Antidotes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D008706:Methemoglobin; D012264:Ribonucleotide Reductases; D008751:Methylene Blue