Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity

Richard Drachtman, Peter D. Cole, Carla B. Golden, S. Jill James, Stepan Melnyk, Joseph Aisner, Barton A. Kamen

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration: Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N -methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPIC) with coulometric eletrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0. 93 μM) than in asymptomatic patients (n = 11, median 0.2 μM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.

Original languageEnglish (US)
Pages (from-to)319-327
Number of pages9
JournalPediatric Hematology and Oncology
Volume19
Issue number5
DOIs
StatePublished - Jun 25 2002

Fingerprint

Dextromethorphan
Methotrexate
Homocysteine
Therapeutics
N-Methyl-D-Aspartate Receptors
Dysarthria
Aptitude
Hemiplegia
Poisons
Controlled Clinical Trials
Vascular Endothelium
Neurologic Manifestations
Mood Disorders
Folic Acid
Headache

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Pediatrics, Perinatology, and Child Health

Cite this

Drachtman, Richard ; Cole, Peter D. ; Golden, Carla B. ; James, S. Jill ; Melnyk, Stepan ; Aisner, Joseph ; Kamen, Barton A. / Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. In: Pediatric Hematology and Oncology. 2002 ; Vol. 19, No. 5. pp. 319-327.
@article{2fef34c995194a6ba34c28848804236f,
title = "Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity",
abstract = "Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration: Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N -methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPIC) with coulometric eletrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0. 93 μM) than in asymptomatic patients (n = 11, median 0.2 μM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.",
author = "Richard Drachtman and Cole, {Peter D.} and Golden, {Carla B.} and James, {S. Jill} and Stepan Melnyk and Joseph Aisner and Kamen, {Barton A.}",
year = "2002",
month = "6",
day = "25",
doi = "https://doi.org/10.1080/08880010290057336",
language = "English (US)",
volume = "19",
pages = "319--327",
journal = "Pediatric Hematology and Oncology",
issn = "0888-0018",
publisher = "Informa Healthcare",
number = "5",

}

Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. / Drachtman, Richard; Cole, Peter D.; Golden, Carla B.; James, S. Jill; Melnyk, Stepan; Aisner, Joseph; Kamen, Barton A.

In: Pediatric Hematology and Oncology, Vol. 19, No. 5, 25.06.2002, p. 319-327.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity

AU - Drachtman, Richard

AU - Cole, Peter D.

AU - Golden, Carla B.

AU - James, S. Jill

AU - Melnyk, Stepan

AU - Aisner, Joseph

AU - Kamen, Barton A.

PY - 2002/6/25

Y1 - 2002/6/25

N2 - Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration: Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N -methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPIC) with coulometric eletrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0. 93 μM) than in asymptomatic patients (n = 11, median 0.2 μM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.

AB - Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration: Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N -methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPIC) with coulometric eletrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0. 93 μM) than in asymptomatic patients (n = 11, median 0.2 μM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.

UR - http://www.scopus.com/inward/record.url?scp=0036281751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036281751&partnerID=8YFLogxK

U2 - https://doi.org/10.1080/08880010290057336

DO - https://doi.org/10.1080/08880010290057336

M3 - Article

VL - 19

SP - 319

EP - 327

JO - Pediatric Hematology and Oncology

JF - Pediatric Hematology and Oncology

SN - 0888-0018

IS - 5

ER -