A Controlled One-Year Trial of Dextromethorphan in Amyotrophic Lateral Sclerosis

Blin, Olivier; Jp, Azulay; Desnuelle, Claude; Billé-Turc, F; Braguer, D.; Besse, D; Branger, E; Crevat, A.; Serratrice, G; Jy, Pouget

doi:10.1097/00002826-199619020-00009

Cited by 38 publications

(14 citation statements)

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“…A second 1-year trial (N ϭ 49) showed no significant differences in rate of disease progression between DM-(1.5 mg/kg/d) and placebo-treated patients. 69 Finally, in a third ALS study (N ϭ 14) no clinical or neurophysiologic parameter (relative number of axons, and compound muscle action potentials) improvements were found with DM in a 12-week placebo-controlled, crossover study (150 mg/d), followed by an up to 6 months open trial (300 mg/d). 70 As noted above, preclinical studies have established that considerably higher doses (about 10 -75 mg/kg, oral) are required for neuroprotective effects (Table 1).…”

Section: Clinical Findings For Dmmentioning

confidence: 92%

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

Werling¹,

Lauterbach²,

Calef³

2007

The Neurologist

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Section: Clinical Findings For Dmmentioning

confidence: 92%

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

Werling¹,

Lauterbach²,

Calef³

2007

The Neurologist

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“…The potential efficacy of DM as a neuroprotectant was explored in limited clinical trials in patients with amyotrophic lateral sclerosis, 9,10 Huntington's disease, 11 and Parkinson's disease 12 . Dextromethorphan was also examined in patients with various types of neuropathic pain 13–19 .…”

mentioning

confidence: 99%

Pharmacokinetics of Dextromethorphan After Single or Multiple Dosing in Combination With Quinidine in Extensive and Poor Metabolizers

Pope

Khalil

Berg

et al. 2004

The Journal of Clinical Pharma

103

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Dextromethorphan (DM) pharmacological properties predict that the widely used cough suppressant could be used to treat several neuronal disorders, but it is rapidly metabolized after oral dosing. To find out whether quinidine (Q), a CYP2D6 inhibitor, could elevate and prolong DM plasma profiles, 2 multiple-dose studies identified the lowest oral dose of Q that could be used in a fixed combination with 3 doses of DM. A multiple-dose study in healthy subjects with an extensive or a poor enzyme metabolizer phenotype evaluated the safety and pharmacokinetic profile of a selected fixed-dose combination (AVP-923). Study 1 randomized 46 healthy subjects, who were extensive CYP2D6 metabolizers, to receive 0, 2.5, 10, 25, 50, or 75 mg Q twice daily in combination with 30 mg DM for 7 days. Plasma and urine samples were collected after the first and last doses for the assay of DM, dextrorphan (DX), and Q. Study 2 randomized 65 healthy extensive CYP2D6 metabolizers to 8 groups given twice-daily 45- or 60-mg DM doses combined with 0, 30, 45, or 60 mg Q for 7 days. The effects of increasing Q were not different with doses greater than 25 mg, whereas lower doses showed a dose-related increase in plasma DM concentrations. Urinary ratios of DM/DX showed a Q dose- and time-related increase in the number of subjects converted to the poor metabolizer phenotype that reached 100% on day 3 of dosing with 25 mg Q. Results from both studies indicated that 25 to 30 mg Q is adequate to maximally suppress O-demethylation of DM. Study 3 evaluated 7 extensive metabolizers and 2 poor metabolizers given an oral capsule every 12 hours containing 30 mg Q combined with 30 mg DM. DM plasma AUC values increased in both groups of subjects during the 8-day study. The mean urinary metabolic ratio (DM/DX) increased at least 27-fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers. Safety evaluations, including electrocardiograms, indicated that the combination was well tolerated, with no difference between extensive and poor metabolizer phenotypes.

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“…A recent study with topiramate, which also has an inhibitory effect on AMPA receptors, was unsuccessful as well [96] . A clinical trial with dextromethorphan, an NMDA receptor antagonist, similarly failed [97,98] . The AMPA receptor antagonist LY300164 was tested in a small double-blind, placebo-controlled study.…”

Section: Pharmacotherapy For Excitotoxicity In Alsmentioning

confidence: 99%

Excitotoxicity and Amyotrophic Lateral Sclerosis

Damme¹,

Dewil²,

Robberecht³

et al. 2005

Neurodegener Dis

133

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Since its description by Charcot more than 130 years ago, the pathogenesis of selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains unsolved. Over the years, many pathogenic mechanisms have been proposed. Amongst others these include: oxidative stress, excitotoxicity, aggregate formation, inflammation, growth factor deficiency and neurofilament disorganization. This multitude of contributing factors indicates that ALS is a complex disease and also suggests that ALS is a multifactorial disorder. Excitotoxicity is not the newest and most spectacular hypothesis in the ALS field, but it is undoubtedly one of the most robust pathogenic mechanisms supported by an impressive amount of evidence. Moreover, the therapeutic efficacy of riluzole, the only drug proven to slow disease progression in ALS, is most likely related to its anti-excitotoxic properties. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS and of the possible mechanisms leading to motor neuron death. We will also summarize the intrinsic properties of motor neurons that render these cells particularly vulnerable to excitotoxicity and could explain the selective vulnerability of motor neurons in ALS. All this information could help to develop new and better therapeutic strategies that could protect motor neurons from excitotoxicity.

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A Controlled One-Year Trial of Dextromethorphan in Amyotrophic Lateral Sclerosis

Cited by 38 publications

References 0 publications

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

Pharmacokinetics of Dextromethorphan After Single or Multiple Dosing in Combination With Quinidine in Extensive and Poor Metabolizers

Excitotoxicity and Amyotrophic Lateral Sclerosis

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