DOI: 10.1002/ana.410360619. High‐dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies

High‐dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies

10.1002/ana.410360619

Crossref journal-article

Wiley

Annals of Neurology (311)

Abstract

AbstractMuch interest has focused on the role of glutamate‐mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high‐dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N‐methyl‐D‐aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light‐headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long‐term administration of high‐dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.

Bibliography

Hollander, D., Pradas, J., Kaplan, R., McLeod, H. L., Evans, W. E., & Munsat, T. L. (1994). Highâdose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies. Annals of Neurology, 36(6), 920â924. Portico.

Authors 6

Dave Hollander (first)
Jesus Pradas (additional)
Richard Kaplan (additional)
Howard L. McLeod (additional)
William E. Evans (additional)
Theodore L. Munsat (additional)

References 34 Referenced 54

10.1002/ana.410280103
WatkinsK Krogsgaard‐LarsenP HonoreKStructure‐activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists.Trends Pharmacol Sci1991(special report):4–12
10.1002/jps.2600660740
{'key': 'e_1_2_1_5_2', 'first-page': '713', 'article-title': 'Dextrorphan and levorphanol selectively block N‐methyl‐D‐aspartate receptor‐mediated neurotoxicity on cortical neurons', 'volume': '242', 'author': 'Choi K', 'year': '1987', 'journal-title': 'J Pharmacol Exp Ther'} / J Pharmacol Exp Ther / Dextrorphan and levorphanol selectively block N‐methyl‐D‐aspartate receptor‐mediated neurotoxicity on cortical neurons by Choi K (1987)
10.1016/0014-2999(85)90755-1
10.1161/01.STR.19.9.1112
{'key': 'e_1_2_1_8_2', 'first-page': '193', 'article-title': 'Dextromethorphan protects against cerebral infarction in a rat model of hypoxia‐ischemia', 'volume': '89', 'author': 'Prince K', 'year': '1988', 'journal-title': 'Neurosci Lett'} / Neurosci Lett / Dextromethorphan protects against cerebral infarction in a rat model of hypoxia‐ischemia by Prince K (1988)
10.1016/0014-2999(88)90707-8
{'key': 'e_1_2_1_10_2', 'first-page': '144', 'article-title': 'Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro', 'volume': '466', 'author': 'Monger K', 'year': '1988', 'journal-title': 'Brain Res'} / Brain Res / Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro by Monger K (1988)
10.1016/0378-5173(83)90092-3
{'key': 'e_1_2_1_12_2', 'first-page': '283', 'article-title': 'Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects', 'volume': '65', 'author': 'Aylward K', 'year': '1984', 'journal-title': 'Eur J Respir Dis'} / Eur J Respir Dis / Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects by Aylward K (1984)
{'key': 'e_1_2_1_13_2', 'first-page': '492', 'article-title': 'Pharmacokinetics of dextromethorphan and dextrophan: a single dose comparison of three preparations in human volunteers', 'volume': '25', 'author': 'Silvasti K', 'year': '1987', 'journal-title': 'Int J Clin Pharmacol Ther Toxicol'} / Int J Clin Pharmacol Ther Toxicol / Pharmacokinetics of dextromethorphan and dextrophan: a single dose comparison of three preparations in human volunteers by Silvasti K (1987)
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{'issue': '1', 'key': 'e_1_2_1_26_2', 'first-page': '393', 'article-title': 'Dextromethorphan in the treatment of ALS: a pilot study', 'volume': '4', 'author': 'Appelbaum K', 'year': '1991', 'journal-title': 'Neurology'} / Neurology / Dextromethorphan in the treatment of ALS: a pilot study by Appelbaum K (1991)
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10.1038/271557a0

Dates

Type	When
Created	20 years, 8 months ago (Jan. 1, 2005, 11:10 a.m.)
Deposited	1 year, 10 months ago (Oct. 24, 2023, 2:47 a.m.)
Indexed	4 days, 8 hours ago (Sept. 3, 2025, 6:09 a.m.)
Issued	30 years, 9 months ago (Dec. 1, 1994)
Published	30 years, 9 months ago (Dec. 1, 1994)
Published Online	20 years, 10 months ago (Oct. 8, 2004)
Published Print	30 years, 9 months ago (Dec. 1, 1994)

Funders 0

None

BibTeX

@article{Hollander_1994, title={High‐dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies}, volume={36}, ISSN={1531-8249}, url={http://dx.doi.org/10.1002/ana.410360619}, DOI={10.1002/ana.410360619}, number={6}, journal={Annals of Neurology}, publisher={Wiley}, author={Hollander, Dave and Pradas, Jesus and Kaplan, Richard and McLeod, Howard L. and Evans, William E. and Munsat, Theodore L.}, year={1994}, month=dec, pages={920–924} }

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