Safety, Tolerability, and Pharmacokinetics of the
            <i>N</i>
            -Methyl-
            <scp>d</scp>
            -Aspartate Antagonist Dextrorphan in Patients With Acute Stroke

Albers, Gregory W.; Atkinson, Richard; Kelley, Roger E.; Rosenbaum, Daniel M.

doi:10.1161/01.str.26.2.254

Cited by 169 publications

(83 citation statements)

References 14 publications

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“…In an ascending-dose trial of dextrorphan begun within 48 hours in patients with mild-to-moderate hemispheric stroke, a variety of dose-related reversible adverse events commonly occurred, including nausea and vomiting, somnolence, hallucinations, agitation, and rapid-onset symtomatic hypotension. The highest infusion rates induced deep stupor or apnea (Albers et al, 1995). The development of MK-801 was also abandoned after early-phase clinical trial experience; although these results were never published, it is commonly assumed that MK-801 also induced dose-limiting neuropsychological adverse events (Olney, 1994).…”

Section: Non-competitive Nmda Antagonismmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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Section: Non-competitive Nmda Antagonismmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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“…25 The noncompetitive NMDA antagonist dextrorphan was also evaluated in a pilot study. 26 Patients were enrolled in this study within 48 h of the onset of hemispheric cerebral infarction. As with Selfotel, adverse effects of dextrorphan occurred in a dose-dependent manner, including agitation, confusion, hallucinations, nystagmus, somnolence, nausea, and vomiting.…”

Section: Table 2 Results From Venus Study Subgroup Analyses Of Patiementioning

confidence: 99%

Clinical trials for cytoprotection in stroke

Labiche

Grotta

2004

Neurotherapeutics

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Summary:To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-totreat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

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“…Dextromethorphan (DM), on the other hand, is a widely used antitussive agent, which has been found to also be an allosteric NMDA receptor antagonist species. 16,17,23,30,31 Cannoll et al observed that DM acts on receptors in brain stem regions, including the nucleus of the solitary tract, the nucleus ambiguus, and hypoglossal nuclei, 32 all with links to ventilatory control. 26 In the present studies, DM administration in Z rats did not produce any of the side effects that were observed with MK-801.…”

Section: Discussionmentioning

confidence: 99%

“…26 In the present studies, DM administration in Z rats did not produce any of the side effects that were observed with MK-801. Since DM has been shown to have safer and lower toxicological effects in other species compared to MK-801, 23,30 and from our own preliminary observations in Z rats, DM was deemed a suitable agent. In the present study, the ventilatory response to hypoxia noted at a dose of 10 mgakg DM in lean Z rats was similar to responses obtained with other NMDA receptor antagonists in piglets, 11 in dogs 12 and in rats.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

2001

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BACKGROUND: Ventilation in response to hypoxia is reduced in some obese humans and is believed to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS). Ventilation in response to hypoxic exposure is closely related to the release of excitatory neurotransmitters, in particular glutamate, acting speci®cally on N-methyl-D-aspartate (NMDA) receptors. OBJECTIVES: The aim of the present study was to investigate whether NMDA receptor-mediated mechanisms are responsible for the altered ventilatory response to sustained hypoxia observed in obese Zucker (Z) rats. SUBJECTS: Seven lean and seven 15-week-old obese male Z rats were studied. MEASUREMENTS: Ventilation (V Ç E ) at rest and during 30 min sustained hypoxic (10% O 2 ) exposure was measured by the barometric method. V Ç E was assessed following the blinded-random administration of equal volumes of either saline (vehicle) or dextromethorphan (DM, 10 mgakg), a non-competitive glutamate NMDA receptor antagonist. RESULTS: DM had no effects on resting V Ç E in both lean and obese rats during room air breathing. Lean rats treated with DM exhibited a signi®cant (P`0.05) depression in V Ç E , V T , and V T aT I during either the early (5 min) or the late phase (30 min) of ventilatory response to sustained hypoxia. In contrast, DM administration in obese rats did not change V Ç E , V T , or V T aT I during the early phase of ventilatory response to hypoxia. During the late phase of ventilatory response to hypoxia. obese rats treated with DM exhibited a similar depression in V Ç E and V T as observed in lean rats, but had no signi®cant change in V T aT I during the 30 min hypoxic exposure. CONCLUSION: Our ®ndings indicate that altered glutamatergic mechanisms acting on NMDA receptors are partially responsible for a blunted early phase of ventilatory response to hypoxia noted in obese rats and also contribute to their reduced neural respiratory drive.

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Safety, Tolerability, and Pharmacokinetics of the N -Methyl- d -Aspartate Antagonist Dextrorphan in Patients With Acute Stroke

Cited by 169 publications

References 14 publications

Neuroprotection for ischemic stroke: Past, present and future

Neuroprotection for ischemic stroke: Past, present and future

Clinical trials for cytoprotection in stroke

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

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