title: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.
abstract: The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.
authors.affiliation: Pediatric Oncology Branch, Pediatric Oncology Branch, National Cancer Institute, 10 Center Dr., Bldg. 10, Rm. 13C103, Bethesda, MD 20892-1920, USA. bw42y@nih.gov
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Aiman
authors.initials: A
authors.lastname: Shalabi
authors.forename: Matthew
authors.initials: M
authors.lastname: Boron
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Brien
authors.forename: Diane E
authors.initials: DE
authors.lastname: Cole
authors.forename: Nalini
authors.initials: N
authors.lastname: Jayaprakash
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Valerie
authors.initials: V
authors.lastname: Castle
authors.forename: Karin
authors.initials: K
authors.lastname: Muraszko
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Moertel
authors.forename: Robert
authors.initials: R
authors.lastname: Trueworthy
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hermann
authors.forename: Ali
authors.initials: A
authors.lastname: Moussa
authors.forename: Stuart
authors.initials: S
authors.lastname: Hinton
authors.forename: Gregory
authors.initials: G
authors.lastname: Reaman
authors.forename: David
authors.initials: D
authors.lastname: Poplack
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D001943:Breast Neoplasms / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004322:Drainage; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D008508:Medication Errors; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D008875:Middle Aged; D009369:Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011994:Recombinant Proteins / Q000627:therapeutic use; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate