dextromethorphan and Seizures

dextromethorphan has been researched along with Seizures* in 44 studies

Reviews

1 review(s) available for dextromethorphan and Seizures

ArticleYear
Neuropsychotoxicity of abused drugs: potential of dextromethorphan and novel neuroprotective analogs of dextromethorphan with improved safety profiles in terms of abuse and neuroprotective effects.
    Journal of pharmacological sciences, 2008, Volume: 106, Issue:1

    Drug abuse involving dextromethorphan, an antitussive, has been a social problem in various geographic locations since the 1960s. Ironically, high doses of the drug confer neuroprotective activity with central nervous system and behavioral effects. Accumulating evidence suggests that metabolism to phencyclidine-like dextrorphan is not essential for the neuroprotective activity of dextromethorphan. Here, we review the neuroprotective properties of dextromethorphan and its potential for abuse and the potential neuroprotective effects of the drug's analogs and 3-hydroxymorphinan, a metabolite of dextromethorphan. These compounds may provide a novel therapeutic direction for the treatment of neurodegenerative diseases such as convulsive or parkinsonian-like disorders.

    Topics: Animals; Antitussive Agents; Behavior, Animal; Brain Ischemia; Central Nervous System; Dextromethorphan; Humans; Neuroprotective Agents; Parkinson Disease; Seizures; Structure-Activity Relationship; Substance-Related Disorders

2008

Other Studies

43 other study(ies) available for dextromethorphan and Seizures

ArticleYear
N-Substituted-3-alkoxy-derivatives of dextromethorphan are functional NMDA receptor antagonists in vivo: Evidence from an NMDA-induced seizure model in rats.
    Pharmacology, biochemistry, and behavior, 2021, Volume: 203

    Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([

    Topics: Alcohols; Animals; Anticonvulsants; Binding Sites; Dextromethorphan; Dextrorphan; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Infusions, Intraventricular; Ligands; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Seizures; Sigma-1 Receptor; Treatment Outcome

2021
Effect of dextromethorphan/quinidine on pentylenetetrazole- induced clonic and tonic seizure thresholds in mice.
    Neuroscience letters, 2020, 06-11, Volume: 729

    This study aimed to investigate the effects of dextromethorphan (DM) or dextromethorphan/quinidine (DM/Q) against pentylenetetrazole (PTZ)- induced seizure threshold in mice and the probable involvement of N-methyl d-aspartate (NMDA), sigma-1 and serotonin 1A (5-HT. NMRI male mice (25-30 g) received quinidine (10, 20, and 30 mg/kg), DM (5, 10, 25, and 50 mg/kg) or DM/Q (10/20, 25/20, and 50/20 mg/kg), 30 min before the infusion of PTZ. ketamine (1 and 5 mg/kg), BD-1047 (2.5 and 5 mg/kg) or WAY-100635 (0.5 and 1 mg/kg) were administrated as pre-treatment 30 min before the selected dose of DM/Q. Seizures were induced by intravenous PTZ infusion. All data were presented as means ± S.E.M. One-way ANOVA test was used to determine statistical significance (p < 0.05).. DM (25 and 50 mg/kg) significantly increased PTZ- induced seizure threshold. DM/Q at doses of 10/20 and 25/20 mg/kg had anticonvulsant effect, while at a dose of 50/20 mg/kg attenuated anticonvulsant effect of DM 50 mg/kg. Ketamine (5 mg/kg) or WAY-100635 (1 mg/kg) potentiated, while BD-1047 (2.5 and 5 mg/kg) attenuated the anticonvulsant effect of DM/Q 10/20 mg/kg.. The results of present study demonstrate that combination with quinidine potentiates the anticonvulsant effect of DM at lower doses, while attenuates it at higher dose. Meanwhile, the effects of DM/Q on seizure activity likely involve an interaction with NMDA, the sigma-1 or the 5-HT

    Topics: Animals; Anticonvulsants; Dextromethorphan; Dose-Response Relationship, Drug; Male; Mice; Pentylenetetrazole; Quinidine; Receptors, N-Methyl-D-Aspartate; Seizures

2020
KCNT1-positive epilepsy of infancy with migrating focal seizures successfully treated with nonnarcotic antitussive drugs after treatment failure with quinidine: A case report.
    Brain & development, 2020, Volume: 42, Issue:8

    Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic encephalopathies resistant to antiepileptic drugs, therefore carrying an extremely poor neurodevelopmental outcome. KCNT1, encoding for a sodium-activated potassium channel (K. Our case was an infant diagnosed with EIMFS with confirmed mutation in KCNT1 gene. Quinidine therapy was started as early as 9 months old. Within the first month of treatment, the number of seizures reduced to about one third. However, seizure-free state was not obtained and his neuropsychological development remained severely delayed. After 16 months of treatment, quinidine had to be discontinued because of cardiac side effects. At 27 months of age, however, his seizures suddenly stopped and he remained seizure-free for five days. This coincided with the prescription of tipepidine, a commonly used antitussive, administered for his persistent cough. Reduction in seizure frequency was also observed with dextromethorphan, another conventional antitussive drug. Although the relation between these treatments and his symptom improvement is a matter of elucidation, there is a possibility that these nonnarcotic antitussive drugs might play a role in the treatment of EIFMS.

    Topics: Antitussive Agents; Dextromethorphan; Electroencephalography; Epilepsy; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Nerve Tissue Proteins; Piperidines; Potassium Channels, Sodium-Activated; Quinidine; Seizures; Treatment Failure; Treatment Outcome

2020
[Hemiconvulsion-hemiplegia-epilepsy syndrome: case report and use of dextromethorphan].
    Revista de neurologia, 2019, Dec-01, Volume: 69, Issue:11

    Síndrome de hemiconvulsión-hemiplejía-epilepsia: caso clínico y uso de dextrometorfano.

    Topics: Child; Dextromethorphan; Epilepsy; Female; Hemiplegia; Humans; Seizures

2019
MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.
    Toxicology and applied pharmacology, 2017, 11-01, Volume: 334

    Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

    Topics: Animals; Antitussive Agents; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

2017
Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors.
    Epilepsy & behavior : E&B, 2016, Volume: 65

    Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10-100mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3mg/kg), while the inducible NOS inhibitor, aminoguanidine (100mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60mg/kg) blunted the anticonvulsant effect of DM (100mg/kg). Also, NMDA antagonists, ketamine (0.5mg/kg) and MK-801 (0.05mg/kg), augmented the anticonvulsant effect of DM (3mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.

    Topics: Animals; Anticonvulsants; Dextromethorphan; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Seizures; Treatment Outcome

2016
Dual Therapeutic Effects of C-10068, a Dextromethorphan Derivative, Against Post-Traumatic Nonconvulsive Seizures and Neuroinflammation in a Rat Model of Penetrating Ballistic-Like Brain Injury.
    Journal of neurotrauma, 2015, Oct-15, Volume: 32, Issue:20

    Post-traumatic seizures can exacerbate injurious outcomes of severe brain trauma, yet effective treatments are limited owing to the complexity of the pathology underlying the concomitant occurrence of both events. In this study, we tested C-10068, a novel deuterium-containing analog of (+)-N-methyl-3-ethoxymorphinan, in a rat model of penetrating ballistic-like brain injury (PBBI) and evaluated the effects of C-10068 on PBBI-induced nonconvulsive seizures (NCS), acute neuroinflammation, and neurofunctional outcomes. NCS were detected by electroencephalographic monitoring. Neuroinflammation was evaluated by immunohistochemical markers, for example, glial fibrillary acidic protein and major histocompatibility complex class I, for activation of astrocytes and microglia, respectively. Neurofunction was tested using rotarod and Morris water maze tasks. Three infusion doses of C-10068 (1.0, 2.5, and 5.0 mg/kg/h × 72 h) were tested in the antiseizure study. Neuroinflammation and neurofunction were evaluated in animals treated with 5.0 mg/kg/h × 72 h C-10068. Compared to vehicle treatment, C-10068 dose dependently reduced PBBI-induced NCS incidence (40-50%), frequency (20-70%), and duration (30-82%). The most effective antiseizure dose of C-10068 (5.0 mg/kg/h × 72 h) also significantly attenuated hippocampal astrocyte activation and perilesional microglial reactivity post-PBBI. Within C-10068-treated animals, a positive correlation was observed in reduction in NCS frequency and reduction in hippocampal astrocyte activation. Further, C-10068 treatment significantly attenuated astrocyte activation in seizure-free animals. However, C-10068 failed to improve PBBI-induced motor and cognitive functions with the dosing regimen used in this study. Overall, the results indicating that C-10068 exerts both potent antiseizure and antiinflammatory effects are promising and warrant further investigation.

    Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Astrocytes; Behavior, Animal; Dextromethorphan; Disease Models, Animal; Electroencephalography; Excitatory Amino Acid Antagonists; Head Injuries, Penetrating; Hippocampus; Inflammation; Male; Microglia; Rats; Rats, Sprague-Dawley; Seizures

2015
Efficacy of dextromethorphan and cyclosporine a for acute encephalopathy.
    Pediatric neurology, 2013, Volume: 48, Issue:3

    Acute encephalopathy with biphasic seizures and late reduced diffusion was recently established clinicoradiologically as an encephalopathy syndrome. The outcome of this encephalopathy is characterized by a low mortality rate and high incidence of neurologic sequelae. Although the exact pathogenesis of this encephalopathy is uncertain, excitotoxic injury with delayed neuronal death is proposed. On the basis of this hypothesis, we tried a combination therapy of N-methyl-D-aspartate receptor antagonist, dextromethorphan, and apoptosis inhibitor, cyclosporine A, in four patients with acute encephalopathy with biphasic seizures and late reduced diffusion. All patients recovered except for hyperactivity in one patient. Furthermore, an additional four patients with near-miss encephalopathy, who showed mild disturbance of consciousness at 24 hours after prolonged febrile seizures associated with exanthem subitum, recovered without secondary seizures by the early administration of dextromethorphan. The combination regimen of dextromethorphan and cyclosporine A could be effective for the treatment and prevention of acute encephalopathy with biphasic seizures and late reduced diffusion.

    Topics: Cyclosporine; Dextromethorphan; Drug Therapy, Combination; Encephalitis; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Female; Humans; Infant; Male; Receptors, N-Methyl-D-Aspartate; Seizures; Treatment Outcome

2013
Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia.
    Brain & development, 2012, Volume: 34, Issue:1

    Nonketotic hyperglycinemia (NKH), or glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme system. In neonatal-onset NKH, patients manifest lethargy, hypotonia, apnea, and intractable epileptic seizures that are not specific to this disease. We experienced a 6-year-old girl with spastic quadriplegia, intractable epilepsy, and mental retardation, all initially regarded as sequelae of neonatal meningitis. The seizure frequency was transiently increased when valproate was started. Head MRI revealed progressive brain atrophy and white matter loss with high intensity signals on T2-weighted and diffusion-weighted images, which prompted us to conduct further metabolic workups. High glycine levels led us to suspect NKH, and we confirmed this diagnosis by the non-invasive, (13)C-glycine breath test. DNA sequencing revealed novel Leu885Pro/Trp897Cys mutations in the glycine decarboxylase gene that were transmitted from both parents. Sodium benzoate and dextromethorphan dramatically decreased her hypertonicity. Our case shows that paradoxical increases in seizure frequency following valproate can be a clue for a diagnosis of NKH, and that a correct diagnosis of NKH can greatly alter the quality of life in such patients.

    Topics: Anticonvulsants; Brain; Child; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Humans; Hyperglycinemia, Nonketotic; Seizures; Sodium Benzoate; Valproic Acid

2012
Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses.
    Canadian journal of anaesthesia = Journal canadien d'anesthesie, 2011, Volume: 58, Issue:1

    Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan.. First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored.. Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P < 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P < 0.001 for both comparisons).. At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity.

    Topics: Anesthetics, Local; Animals; Apnea; Bupivacaine; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heart Arrest; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Seizures; Time Factors

2011
Differential alterations of GABA(A) receptor (α1, β2, γ2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: beneficial effect of dextromethorphan.
    Neuroscience letters, 2011, Feb-01, Volume: 489, Issue:1

    Although prenatal morphine exposure experimentally induces seizures in rat offspring, underlying mechanisms remain unclear. This study addresses whether prenatal morphine exposure altered subunit compositions of γ-aminobutyric acid receptor subtype A (GABA(A)R) in the hippocampal CA1 area and temporal cortex and increased seizure susceptibility of young rat offspring, at a representative age (postneonatal days 14; P14). Therapeutic efficacy of dextromethorphan (a noncompetitive antagonist of N-methyl-d-aspartate receptors (NMDARs)), in such offspring was also evaluated. From P7 to 14, Sprague-Dawley rat offspring were intraperitoneally (ip) injected a representative dose of dextromethorphan (3mg/kg) twice a day. At P14, some offspring were ip injected pentylenetetrazol to estimate seizure susceptibility, while the others were studied for GABA(A)R subunit (α1, β2, γ2) expression. Prenatal morphine exposure caused the up-regulated α1 subunit and down-regulated β2/γ2 subunit expression of GABA(A)R within hippocampus and temporal cortex in rat offspring associated to increase seizure susceptibility. The magnitudes of upregulated α1 subunit and downregulated β2 subunit expression in the hippocampus were greater than which in the temporal cortex. The use of dextromethorphan markedly reversed the prenatal morphine-induced alterations, indicating the possible therapeutic actions of dextromethorphan. These results suggest that the altered subunit compositions (α1, β2, γ2) of GABA(A)R in the hippocampal CA1 area and temporal cortex may contribute, at least in part, to the increased seizure susceptibility of rat offspring subjected to prenatal morphine exposure. More importantly, dextromethorphan may be a promising clinical agent acting against these alterations.

    Topics: Animals; Blotting, Western; Brain; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Morphine Dependence; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures

2011
Effects of dextromethorphan on electroconvulsive therapy.
    Psychiatry and clinical neurosciences, 2009, Volume: 63, Issue:1

    Topics: Adult; Antitussive Agents; Chronic Disease; Cough; Dextromethorphan; Electroconvulsive Therapy; Humans; Inpatients; Male; Receptors, N-Methyl-D-Aspartate; Seizures

2009
Effect of the NMDA-receptor antagonist dextromethorphan in infant rat pneumococcal meningitis.
    Current drug metabolism, 2008, Volume: 9, Issue:1

    Excitatory amino acids (EAA) and particularly glutamate toxicity have been implicated in the pathogenesis of neuronal injury occurring in bacterial meningitis by activating the N-methyl-d aspartate (NMDA) receptor complex. Here, we evaluated the effect of adjuvant treatment with the antitussive drug dextromethorphan (DM), a non-competitive NMDA receptor antagonist with neuroprotective potential, in an infant rat model of pneumococcal meningitis. The experiments were carried out in postnatal day 6 (P6) and 11 (P11) animals. Pharmacokinetics of DM and its major metabolite dextrorphan (DO) were performed for dose finding. In our study, DM did not alter clinical parameters (clinical score, motor activity, incidence of seizures, spontaneous mortality) and cortical neuronal injury but increased the occurrence of ataxia (P<0.0001). When DM treatment was started at the time of infection (DM i.p. 15 mg/kg at 0, 4, 8 and 16 hours (h) post infection) in P11 animals, an aggravation of apoptotic neuronal death in the hippocampal dentate gyrus was found (P<0.05). When treatment was initiated during acute pneumococcal meningitis (DM i.p. 15 mg/kg at 12 and 15 h and 7.5 mg/kg at 18 and 21 h after infection), DM had no effect on the extent of brain injury but reduced the occurrence of seizures (P<0.03). We conclude that in this infant rat model of pneumococcal meningitis interference of the EEA and NMDA pathway using DM causes ataxia, attenuates epileptic seizures and increases hippocampal apoptosis, but is not effective in protecting the brain from injury.

    Topics: Animals; Apoptosis; Ataxia; Brain; Dextromethorphan; Dose-Response Relationship, Drug; Meningitis, Pneumococcal; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

2008
Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats.
    Neurochemistry international, 2007, Volume: 50, Issue:6

    We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

    Topics: Adrenergic alpha-Antagonists; Animals; Avoidance Learning; Behavior, Animal; Dextromethorphan; Ethylenediamines; Immunohistochemistry; Learning Disabilities; Maze Learning; Memory; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Phencyclidine; Receptors, sigma; Seizures; Sigma-1 Receptor; Trimethyltin Compounds

2007
Are false-positive phencyclidine immunoassay instant-view multi-test results caused by overdose concentrations of Ibuprofen, metamizol, and dextromethorphan?
    Therapeutic drug monitoring, 2007, Volume: 29, Issue:5

    Topics: Anti-Inflammatory Agents, Non-Steroidal; Antitussive Agents; Child, Preschool; Dextromethorphan; Diagnosis, Differential; Dipyrone; Drug Overdose; False Positive Reactions; Female; Humans; Ibuprofen; Immunoassay; Infant, Newborn; Male; Phencyclidine; Seizures

2007
The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan.
    British journal of pharmacology, 2005, Volume: 144, Issue:7

    In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.

    Topics: Animals; Dextromethorphan; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Morphinans; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures

2005
Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice.
    Life sciences, 2003, Jan-03, Volume: 72, Issue:7

    The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX) on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM or DX (5 or 10 microg/0.5 microl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 microg/0.07 microl) in a dose-related manner. DM or DX pretreatment significantly attenuated kainic acid-induced increases in AP-1 DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX. Since the high-affinity DM binding sites are recognized as being identical to the sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the sigma-1 receptor antagonist BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related manner. This effect of BD 1047 was more pronounced in the animals treated with DM than in those treated with DX. Combined, our results suggest that metabolism of DM to DX is not essential for DM to exert its effect. They also suggest that DM provides neuroprotection from kainic acid via sigma-1 receptor modulation.

    Topics: Animals; Anticonvulsants; Dextromethorphan; Dextrorphan; DNA; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Injections, Intraventricular; Kainic Acid; Male; Mice; Mice, Inbred DBA; Neurons; Proto-Oncogene Proteins c-fos; Receptors, Opioid, delta; Seizures; Transcription Factor AP-1

2003
New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice.
    Life sciences, 2003, Mar-07, Volume: 72, Issue:16

    Interest in dextromethorphan (DM) has been renewed because of its anticonvulsant and neuroprotective properties. However, DM at supra-antitussive doses can produce psychotomimetic effects in humans. Recently, we demonstrated that DM exerts psychotropic effects in mice [Neurosci. Lett. 288 (2000) 76, Life Sci. 69 (2001) 615]. We synthesized a series of compounds with a modified morphinan ring system, with the intention of developing compounds that retain the anticonvulsant activity with weak psychotropic effects [Bioorg. Med. Chem. Lett. 11 (2001) 1651]. In order to extend our understanding of the pharmacological intervention of these morphinans, we assessed their behavioral effects, and then examined whether they exert protective effects on maximal electroshock convulsions (MES) in mice. Repeated treatment (20 or 40 mg/kg, i.p./day x 7) with DM or dextrorphan (a major metabolite of DM; DX) significantly enhanced locomotor activity in a dose-related manner. This locomotor stimulation was accentuated more in the animals treated with DX, and might be comparable to that of phencyclidine (PCP). By contrast, treatment with a metabolite of DM [3-methoxymorphinan (3MM) or 3-hydroxymorphinan (3HM)], 3-allyloxy-17-methylmorphinan (CPK-5), or 3-cyclopropylmethoxy-17-methylmorphinan (CPK-6) did not significantly alter locomotor activity or patterns. The behavioral effects mediated by these morphinans and PCP paralleled the effects of conditioned place preference. DM, DX, CPK-5, and CPK-6 had anticonvulsant effects against MES, while 3MM and 3HM did not show any anticonvulsant effects. We found that DM, DX, CPK-5 and CPK-6 were high-affinity ligands at sigma(1) receptors, while they all had low affinity at sigma(2) receptors. DX had relatively higher affinity for the PCP sites than DM. By contrast, CPK-5 and CPK-6 had very low affinities for PCP sites, suggesting that PCP sites are not requisites for their anticonvulsant actions. Our results suggest that the new morphinan analogs are promising anticonvulsants that are devoid of PCP-like behavioral side effects, and their anticonvulsant actions may be, in part, mediated via sigma(1) receptors.

    Topics: Animals; Anticonvulsants; Dextromethorphan; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Morphinans; Radioligand Assay; Receptors, sigma; Seizures

2003
Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke.
    Journal of medicinal chemistry, 2002, Aug-15, Volume: 45, Issue:17

    We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice. We found that the hydroxyl function in the 4'-position is crucial for improving the sodium channel blocking properties. Moreover, the stereochemistry and the topology of the N-linked side chain also influence this interaction. Indeed, the affinity is improved by an aromatic substitution in the side chain. By modifying the N substituent and the substitution pattern of the hydroxyl function, we were able to discover (2R)-[2alpha,3(S),6alpha]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride. This compound was chosen as the best candidate for further pharmacological investigations.

    Topics: Animals; Benzomorphans; Cerebral Cortex; Corpus Striatum; Crystallography, X-Ray; Electroshock; Glutamic Acid; In Vitro Techniques; Male; Mice; Neuroprotective Agents; Radioligand Assay; Rats; Seizures; Sodium Channel Blockers; Stroke; Structure-Activity Relationship; Thromboembolism; Veratridine

2002
Consultation with the specialist: the central serotonin syndrome: paradigm for psychotherapeutic misadventure.
    Pediatrics in review, 2002, Volume: 23, Issue:12

    Topics: Adolescent; Amphetamine-Related Disorders; Antidepressive Agents; Antitussive Agents; Anxiety Disorders; Child; Dextromethorphan; Diagnosis, Differential; Drug Interactions; Female; Fluvoxamine; Hallucinogens; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Obsessive-Compulsive Disorder; Seizures; Selective Serotonin Reuptake Inhibitors; Serotonin Agents; Serotonin Syndrome; Sertraline

2002
[Dextromethorphan poisoning].
    Anales espanoles de pediatria, 2002, Volume: 57, Issue:5

    Topics: Antitussive Agents; Dextromethorphan; Humans; Infant; Male; Seizures

2002
Effects of dextromethorphan on the seizures induced by kainate and the calcium channel agonist BAY k-8644: comparison with the effects of dextrorphan.
    Behavioural brain research, 2001, Volume: 120, Issue:2

    BAY k-8644 (an L-type Ca(2+) channel agonist of the dihydropyridine class) is recognized as a potent convulsant agent. In this study, we used BAY k-8644 to explore the effects of dextromethorphan (DM) and its major metabolite, dextrorphan (DX), on the (pro)convulsant activity regulated by calcium channels. BAY k-8644 (2 mg/kg, s.c) potentiated seizures induced in rats by kainic acid (KA) (10 mg/kg, i.p.). DM appears more efficacious than DX in attenuation of KA-induced seizures. The anticonvulsant effect of a low dose (12.5 mg/kg, s.c.) of DM was reversed by BAY k-8644 (2 mg/kg) challenge. In contrast, BAY k-8644 (1 or 2 mg/kg) did not significantly affect an anticonvulsant effect from a higher dose (25 mg/kg) of either DM or DX. Intracerebroventricular injection of BAY k-8644 (37.5 microg) significantly induced seizures in mice. DM (12.5 or 25 mg/kg) pretreatment more significantly attenuated seizures evoked by BAY k-8644 than did DX (12.5 or 25 mg/kg). Furthermore, seizure activity induced by KA or BAY k-8644 was consistent with respective activator protein-1 DNA binding activity of the hippocampus. Therefore, our results suggest that the anticonvulsant effects of the morphinans involve, at least in part, the L-type calcium channel. They also suggest that DM is a more potent anticonvulsant than DX in the KA and BAY k-8644 seizure models.

    Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Dextromethorphan; Dextrorphan; Excitatory Amino Acid Agonists; Kainic Acid; Male; Mice; Mice, Inbred DBA; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures; Transcription Factor AP-1

2001
Effects of N-methyl-D-aspartate receptor subunit antagonists on regulation of susceptibility to audiogenic seizures in rats.
    Neuroscience letters, 2000, Jul-14, Volume: 288, Issue:2

    Rats become susceptible to audiogenic seizures (AS) when they are exposed to intense noise during a certain critical period of development (priming). Antagonism of N-methyl-D-aspartate (NMDA) receptor NR2B subunit by injecting an antagonist ifenprodil at priming enhanced the later susceptibility to AS. An weak NR2A antagonist, dextromethorphan, did not show such effects while it significantly suppressed the manifestation of AS in already susceptible post-weaning (primed) rats. These results indicate that NR2B plays an important role in the developmental regulation of the auditory system involved in AS but this subunit has a minor relevance to the manifestation of AS in the later life.

    Topics: Animals; Dextromethorphan; Disease Susceptibility; Epilepsy, Reflex; Excitatory Amino Acid Antagonists; Female; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

2000
Dextromethorphan attenuates ethanol withdrawal syndrome in rats.
    Pharmacology, biochemistry, and behavior, 1999, Volume: 62, Issue:3

    The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.

    Topics: Acoustic Stimulation; Animals; Antitussive Agents; Central Nervous System Depressants; Dextromethorphan; Ethanol; Male; Motor Activity; Rats; Rats, Wistar; Seizures; Substance Withdrawal Syndrome

1999
Gamma-aminobutyric acid and glutamic acid receptors may mediate theophylline-induced seizures in mice.
    General pharmacology, 1999, Volume: 32, Issue:3

    The effects of drugs affecting GABA and glutamic acid receptors on theophylline-induced seizures were investigated in mice. Theophylline elicited tonic seizures in mice in a dose dependent manner. Muscimol, DABA and AOAA significantly prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. Baclofen significantly delayed the onset of the tonic seizures induced by theophylline. Bicuculline and picrotoxin significantly shortened the onset and significantly increased the incidence of seizures induced by a low dose of theophylline and also significantly antagonized muscimol-attenuating effect against theophylline seizures. N-methyl-DL-aspartic acid significantly shortened the onset and significantly increased the incidence of seizures elicited by a low dose of theophylline. D-(-)-2-amino-phosphonopentanoic acid effectively delayed the onset and significantly decreased the incidence of seizures elicited by theophylline and also significantly antagonized the potentiating effect of N-methyl-DL-aspartic acid on seizures induced by a low dose of theophylline. Dextromethorphan and ketamine profoundly shortened the onset of theophylline-induced seizures. Clonidine effectively prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. These data indicate that GABA(A) and N-methyl-D-aspartic acid receptors may mediate theophylline-elicited tonic seizures in mice.

    Topics: 2-Amino-5-phosphonovalerate; Aminobutyrates; Aminooxyacetic Acid; Animals; Baclofen; Bicuculline; Clonidine; Dextromethorphan; Drug Interactions; Female; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Ketamine; Mice; Muscimol; N-Methylaspartate; Picrotoxin; Receptors, GABA; Receptors, Glutamate; Seizures; Theophylline

1999
Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia.
    The Journal of pediatrics, 1998, Volume: 132, Issue:4

    The objective of this study was to test the hypotheses that reduction of glycine and blocking of the N-methyl-D-aspartate receptor channel complex would be beneficial for both seizure reduction and developmental progress in patients with nonketotic hyperglycinemia.. We administered benzoate (at doses of 500 to 750 mg/kg/day) and dextromethorphan (at doses of 3.5 to 22.5 mg/kg/day) to four infants with nonketotic hyperglycinemia with follow-up of 3 months to 6 years.. Benzoate reduced to normal the glycine concentration in plasma and substantially reduced but did not normalize the glycine concentration in cerebrospinal fluid. Dextromethorphan was a potent anticonvulsant in some but not all patients. There was remarkable interpatient variability in dextromethorphan metabolism. Three patients are living (ages ranging from 4 to 6 years) and are moderately to severely developmentally delayed; two are free of seizures. The third patient, with the slowest development, had intractable seizures for nearly a month before diagnosis, and although seizure-free for 30 months, now has grand-mal seizures. One patient died of intractable seizures at 3 months.. These outcomes suggest that benzoate and dextromethorphan are not uniformly effective in nonketotic hyperglycinemia, but for some patients they improve arousal, decrease or eliminate seizures, and allow for some developmental progress. Trials with additional patients and other receptor channel blockers are warranted.

    Topics: Amino Acid Metabolism, Inborn Errors; Benzoates; Benzoic Acid; Child; Child, Preschool; Dextromethorphan; Female; Follow-Up Studies; Glycine; Humans; Infant; Male; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

1998
Dextromethorphan in nonketotic hyperglycinaemia: metabolic variation confounds the dose-response relationship.
    Journal of inherited metabolic disease, 1997, Volume: 20, Issue:1

    Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cleavage system resulting in seizures and mental retardation. Two prior reports noted an anticonvulsant effect from high-dose dextromethorphan (DM) in this disorder, although the two reported patients demonstrated widely disparate DM requirements and drug levels. We report two children with NKH who also demonstrated disparate and variable DM metabolism which markedly influenced the dose-concentration-response relationship. Levels of DM and its primary metabolite dextrorphan (DX) were utilized to guide DM therapy and exhibited patterns reflective of the extensive and poor metabolizer phenotypes for CYP2D6, the cytochrome P450 isoform responsible for DM metabolism. In the patient who appeared to represent the extensive metabolizer (EM) phenotype, treatment with the non-specific cytochrome P450 inhibitor cimetidine was required to reduce biotransformation of DM to DX and, thus, to increase DM plasma concentrations. In the patient with the apparent poor metabolizer (PM) phenotype, a change in the DM preparation to a sustained-release form and increase in the dosing interval was required to lower DM plasma concentrations. These cases demonstrate the importance of CYP2D6 phenotype in providing safe and effective DM therapy to patients with NKH.

    Topics: Child; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemic Hyperosmolar Nonketotic Coma; Infant, Newborn; N-Methylaspartate; Seizures

1997
Dextromethorphan ameliorates effects of neonatal hypoxia on brain morphology and seizure threshold in rats.
    Brain research. Developmental brain research, 1997, May-20, Volume: 100, Issue:1

    Hypoxic injury to the brain is mediated in part by NMDA receptors. Therefore, NMDA receptor blockade with dextromethorphan (DM), a non-competitive channel blocker, was hypothesized to ameliorate injury even when given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after exposure, cortical thickness and hippocampal area were measured. At 70-90 days of age, approximately two months after exposure, in a separate group of rats, seizure threshold using pentylenetetrazol (PTZ) and passive avoidance learning and retention were determined. There were no gross changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decreased in animals exposed to hypoxia. DM administration prevented this decrease. Hippocampal area was unaffected. Seizure susceptibility in adulthood was increased in animals exposed to hypoxia in the neonatal period. DM prevented the decrease in seizure threshold. There was no difference in passive avoidance learning or retention as a function of neonatal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult.

    Topics: Aging; Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning; Brain; Cerebral Cortex; Dextromethorphan; Hippocampus; Humans; Hypoxia, Brain; Male; Pentylenetetrazole; Rats; Receptors, N-Methyl-D-Aspartate; Reference Values; Seizures

1997
Dextromethorphan blocks opioid peptide gene expression in the rat hippocampus induced by kainic acid.
    Neuropeptides, 1997, Volume: 31, Issue:2

    We have previously shown that dextromethorphan (DM) antagonizes kainic acid (KA)-induced neurotoxicity. Accumulating evidence indicates that the induction of seizure activity causes profound alterations in the levels of hippocampal opioid peptide mRNA. The present study was performed to further explore the effect of DM on KA-induced seizures as measured by hippocampal opioid peptide mRNA levels. Both Northern blot and in situ hybridization methods were used to examine the proenkephalin (PENK) and prodynorphin (PDYN) mRNA levels in the rat hippocampus. The robust seizure activity induced by KA correlated with a significant increase in hippocampal opioid peptide mRNA levels. Pretreatment of rats with DM decreased hippocampal PENK and PDYN mRNA levels and seizure activity induced by KA. Hippocampal PDYN mRNA levels fell quickly but PENK mRNA levels fell rather slowly, indicating that the PENK and PDYN mRNAs are differentially regulated. Our results demonstrate that DM modulates opioid peptide gene expression induced by KA, and that DM protects against KA-induced seizures.

    Topics: Animals; Dextromethorphan; Enkephalins; Gene Expression Regulation; Hippocampus; In Situ Hybridization; Kainic Acid; Male; Neurotoxins; Protein Precursors; Rats; Rats, Inbred F344; RNA, Messenger; Seizures; Transcription, Genetic

1997
Decreased cocaine- and lidocaine-induced seizure response by dextromethorphan and DNQX in rat.
    Brain research, 1997, May-09, Volume: 756, Issue:1-2

    The present study investigated the effect of dextromethorphan and 6,7-dinitroquinoxaline-2,3-dione (DNQX) pre-treatment on the development of cocaine- and lidocaine-induced seizures. The dopaminergic action of cocaine was also studied. The NMDA antagonist dextromethorphan and the non-NMDA (AMPA/kainate) antagonist DNQX both significantly decreased the intensity of the seizure response to intravenous convulsant doses of cocaine and lidocaine individually (20 mg/kg) and in combination (5 mg/kg each). The incidence of seizures in rats receiving cocaine or lidocaine individually was significantly reduced by pre-treatment with dextromethorphan but not DNQX. Haloperidol did not have an effect on the incidence or intensity of seizures induced by cocaine or lidocaine, alone or in combination. The results suggest that local anesthetic-induced convulsive seizures are mediated by excitatory glutamate transmission through both NMDA and non-NMDA receptor systems.

    Topics: Anesthetics, Local; Animals; Cocaine; Dextromethorphan; Excitatory Amino Acid Antagonists; Incidence; Injections, Intravenous; Lidocaine; Male; Narcotics; Quinoxalines; Rats; Rats, Sprague-Dawley; Seizures

1997
The effects of dextromethorphan on kainic acid-induced seizures in the rat.
    Neurotoxicology, 1996,Summer, Volume: 17, Issue:2

    Several studies have shown that dextromethorphan (DM) has both anticonvulsant and proconvulsant effects depending on the animal model. In this study, we examined the effects of DM on three parameters associated with kainic acid (KA)-induced seizures: cell loss in the hippocampus, increased AP-1 DNA binding activity and increased c-Jun and fos-related antigen (FRA) expression. KA administration (8 mg/kg, ip) produced robust behavioral convulsions lasting 4-6 hr. Pretreatment with DM (12.5-75 mg/kg, po) 15 min before KA injections reduced the seizures as well as mortality in a dose-dependent manner. Histological studies revealed a severe loss of cells in the CA1 and CA3 fields of the hippocampus in KA-treated rats. DM pretreatment also reduced this cell loss in a dose-dependent fashion. Biochemical studies showed that DM pretreatment also attenuated the KA-induced increase of AP-1 binding activity and c-Jun/FRA expression in the hippocampus. These results indicate that DM is an effective antagonist of KA.

    Topics: Animals; Blotting, Western; Dextromethorphan; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Inbred F344; Seizures; Transcription Factor AP-1

1996
Dextromethorphan: cellular effects reducing neuronal hyperactivity.
    Epilepsia, 1994, Volume: 35 Suppl 5

    Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and antiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N-methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.

    Topics: Animals; Calcium Channels; Cells, Cultured; Dextromethorphan; Dextrorphan; Electrophysiology; Evoked Potentials; Humans; Ion Channels; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channels

1994
4-Hydroxybutyric aciduria.
    Brain & development, 1994, Volume: 16 Suppl

    The clinical findings in six patients from three families with 4-hydroxybutyric aciduria are described. The onset of disease was in early infancy in all cases. All infants presented with severe global delay and severe hypotonia, and all patients had seizure disorder. Eye findings included optic atrophy in two patients, and retinitis pigmentosa in one. Three patients had choreoathetosis, two had myoclonus and one had severe dystonia. The urine 4-hydroxybutyric acid was 300-1000 times that of normal, and other organic acids related to its further metabolism or to its inhibitory effect on beta-oxidation were also increased. The administration of vigabatrine rapidly reduced the excretion of 4-hydroxybutyric acid promptly, and in the long-term its excretion could be kept at 80-200 times that of normal. However, the clinical course of the disease improved in only two, remained the same in two, and worsened in the remaining two patients.

    Topics: Adult; Anticonvulsants; Brain; Child; Child, Preschool; Dextromethorphan; Female; gamma-Aminobutyric Acid; Humans; Hydroxybutyrates; Infant; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Nervous System Diseases; Seizures; Vigabatrin

1994
Differences in anticonvulsant potency and adverse effects between dextromethorphan and dextrorphan in amygdala-kindled and non-kindled rats.
    European journal of pharmacology, 1993, Jul-20, Volume: 238, Issue:2-3

    The anticonvulsant and adverse effects of dextromethorphan, a non-opioid antitussive, and its metabolite dextrorphan were examined in amygdala-kindled rats. Both drugs have repeatedly been proposed to be functional non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, but they also exert effects distinct from antagonism at NMDA receptors, such as blockade of voltage-gated calcium channels and sigma-site mediated actions. Since recent data have demonstrated that kindled rats are more susceptible to the adverse effects of NMDA receptor antagonists than non-kindled rats, the time course, characteristics and severity of adverse effects of dextromethorphan and dextrorphan were also determined in non-kindled animals. Dextromethorphan dose dependently increased the focal seizure threshold (i.e. the threshold for induction of afterdischarges recorded from the amygdala) in fully kindled rats. This anticonvulsant effect was found at relatively low doses (7.5-15 mg/kg i.p.) which were almost free of any adverse effects. At higher doses, dextromethorphan induced motor impairment and seizures, but no phenyclidine (PCP)-like adverse effects, such as hyperlocomotion or stereotypies. In contrast, such adverse effects were seen after dextrorphan, although only infrequently. Dextrorphan was less potent in inducing anticonvulsant but more potent in inducing motor impairing effects than dextromethorphan in kindled rats. In non-kindled rats, the motor impairment induced by dextrorphan was significantly less severe than in kindled rats, whereas no marked differences between kindled and non-kindled rats were found for dextromethorphan. The data indicate that dextromethorphan and dextrorphan differ in their mechanisms of action. Only dextrorphan exerts effects which are characteristic for NMDA receptor antagonism, whereas the potent anticonvulsant effect of dextromethorphan in presumably unrelated to the NMDA receptor complex.

    Topics: Amygdala; Animals; Anticonvulsants; Dextromethorphan; Dextrorphan; Female; Kindling, Neurologic; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

1993
Dextromethorphan in infantile nonketotic hyperglycinemia.
    The Journal of pediatrics, 1993, Volume: 122, Issue:2

    Topics: Dextromethorphan; Dextrorphan; Glycine; Humans; Infant; Ketosis; Receptors, N-Methyl-D-Aspartate; Seizures

1993
Dextromethorphan and its combination with phenytoin facilitate kindling.
    Neurology, 1993, Volume: 43, Issue:5

    We implanted 20 rats with bipolar electrodes and randomly distributed them into four groups that received intraperitoneal injections of phenytoin (PHT) (20 mg/kg), dextromethorphan (DM) (50 mg/kg), PHT+DM (20 and 50 mg/kg, respectively), or saline (C), 15 minutes before each daily stimulation. The number of stimulations needed to reach stage 3 seizures was 14.4 +/- 1.7 (C); 28 +/- 12 (PHT, p < 0.001); 6.2 +/- 3.9 (DM, p < 0.05); and 7.6 +/- 3.4 (PHT+DM, p < 0.05), suggesting that DM accelerated the expression of kindled seizures. Daily injections of DM and of DM+PHT without stimulation resulted in progressive seizure buildup to stage 3 in 4.8 +/- 6.2 (DM) or in 8 +/- 4.8 (DM+PHT) trials. We demonstrated savings in six kindled animals reinjected after 1 month. These results and previous experimental and clinical data suggest that DM may be epileptogenic when given repeatedly in high doses.

    Topics: Animals; Dextromethorphan; Drug Interactions; Electric Stimulation; Hippocampus; Kindling, Neurologic; Male; Phenytoin; Rats; Rats, Sprague-Dawley; Seizures

1993
Excitatory amino acids and the actions of cocaine.
    Brain research, 1992, Jun-05, Volume: 582, Issue:1

    Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

    Topics: Animals; Caffeine; Cocaine; Dextromethorphan; Dizocilpine Maleate; Haloperidol; Male; Mice; Mice, Inbred Strains; Motor Activity; N-Methylaspartate; Pipecolic Acids; Quinoxalines; Rats; Rats, Inbred Strains; Seizures; Stereoisomerism; Stereotyped Behavior

1992
Effect of orally administered dextromethorphan on theophylline- and pentylenetetrazol-induced seizures in rats.
    Journal of pharmaceutical sciences, 1990, Volume: 79, Issue:12

    Dextromethorphan, widely used as an antitussive, has recently been shown to protect animals against maximal electroshock and excitatory amino acid (N-methyl-D-aspartate)-induced convulsions. Its protective efficacy against theophylline-induced seizures was determined in this investigation in view of the limited effectiveness of presently available anticonvulsants against this manifestation of serious theophylline intoxication. Rats were pretreated with an oral dose of dextromethorphan (50 mg/kg) or saline solution. Fifteen minutes later, the rats were infused intravenously with theophylline [approximately 11 mg/(kg.min)] until the onset of maximal seizures. Pretreatment with dextromethorphan was associated with a significant decrease in the concentrations of theophylline in the cerebrospinal fluid and serum at the pharmacologic endpoint. To further explore this unanticipated effect, a similar experiment was performed with the convulsant pentylenetetrazol (PTZ), which was infused at a rate of approximately 3.4 mg/(kg.min) until the onset of maximal seizures. Dextromethorphan-pretreated animals required a significantly larger dose of PTZ than did controls to produce the first myoclonic jerk, but a significantly smaller dose of the convulsant to produce maximal seizures. Serum and cerebrospinal fluid concentrations of PTZ at onset of maximal seizures were significantly lower in dextromethorphan-treated than in control animals. The proconvulsant activity of dextromethorphan with respect to theophylline-induced maximal seizures is similar to that of phenytoin, and is consistent with other pharmacologic evidence of such similarity.

    Topics: Administration, Oral; Animals; Dextromethorphan; Female; Pentylenetetrazole; Premedication; Rats; Rats, Inbred Lew; Seizures; Theophylline

1990
Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices.
    Neuroscience letters, 1988, Feb-29, Volume: 85, Issue:2

    The antitussive, dextromethorphan (DM), and its metabolite, dextrorphan (DX), were evaluated for antiepileptic properties in vitro. Interictal bursts and prolonged ictal epileptiform afterdischarges, induced by perfusion of guinea pig neocortical brain slices with Mg2+-free solution, were blocked by DX (1-250 microM) or DM (100 microM). Intracellular records showed that these agents blocked N-methyl-D-aspartate (NMDA)-induced depolarizations without altering intrinsic membrane properties. DX blocked NMDA but not quisqualate-evoked multi-unit excitatory responses. DM is a widely available, orally effective drug with low toxicity in antitussive doses, which has antiepileptic and NMDA-antagonist properties in vitro. Its toxicity and effectiveness as an anticonvulsant should be expeditiously examined in clinical trials.

    Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Antitussive Agents; Aspartic Acid; Cerebral Cortex; Dextromethorphan; Dextrorphan; Evoked Potentials; Guinea Pigs; In Vitro Techniques; Levorphanol; Morphinans; N-Methylaspartate; Seizures; Valine

1988
Dextromethorphan inhibits NMDA-induced convulsions.
    European journal of pharmacology, 1988, Jun-22, Volume: 151, Issue:1

    Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.

    Topics: Animals; Anticonvulsants; Aspartic Acid; Dextromethorphan; Dibenzocycloheptenes; Dizocilpine Maleate; Levorphanol; Male; Mice; N-Methylaspartate; Psychomotor Performance; Seizures

1988
Dextromethorphan, a common antitussive, reduces kindled amygdala seizures in the rat.
    Neuroscience letters, 1988, Apr-12, Volume: 86, Issue:3

    Dextromethorphan (DM), a non-prescription antitussive, has anticonvulsant properties and antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in rat spinal and cortical neurons. The effects of daily intraperitoneal injections of DM on amygdala-kindled seizures were examined. DM was found both to prevent the development of full kindling in rats and to decrease seizure intensity in previously fully kindled animals. The findings of this study, combined with the ready availability of DM and its apparent safety in antitussive doses suggest that clinical testing of this drug as an anticonvulsant is warranted.

    Topics: Amygdala; Animals; Antitussive Agents; Dextromethorphan; Kindling, Neurologic; Levorphanol; Male; Rats; Rats, Inbred Strains; Seizures

1988
Dextromethorphan and carbetapentane: centrally acting non-opioid antitussive agents with novel anticonvulsant properties.
    Brain research, 1986, Sep-24, Volume: 383, Issue:1-2

    The non-opioid antitussives dextromethorphan and carbetapentane, the active ingredients of several over-the-counter cough suppressants, provide a dose-related protection against maximal electroshock seizures in rats. Both drugs, which bind with high affinity to the same site in the brain, potentiated the effects of the prototypic antiepileptic drug diphenylhydantoin. We propose that these novel anticonvulsant drugs may represent potentially useful therapeutic agents for the treatment of some forms of epilepsy, either alone or in combination with existing antiepileptic drugs.

    Topics: Animals; Anticonvulsants; Antitussive Agents; Cyclopentanes; Dextromethorphan; Drug Synergism; Electroshock; Levorphanol; Male; Phenytoin; Rats; Rats, Inbred Strains; Seizures

1986
Antitussive activity and other related pharmacological properties of d-3-methyl-N-methylmorphinan (AT-17).
    Arzneimittel-Forschung, 1976, Volume: 26, Issue:3

    Antitussive activity and some other related pharmacological properties of d-3-methyl-N-methylmorphinan were studied. Toxic symptoms in mice and dogs were due to the CNS excitation. Acute toxicity of (AT-17) in mice was slightly (s.c.) or far (p.o.) weaker than that of codeine, but it was three times as toxic as codeine in dogs (i.v.). Antitussive efficacy was about 40% of that of codeine in dogs, whereas 77% as potent as codeine in cats. It showed no relaxing effect on the bronchial muscle of guinea pigs in either normal tone or histamine-induced spasms. It had analgesic effect 1/3 as potent as codeine in mice but it was not antagonized by levallorphan. The prolongation of hexobarbital sleeping time by AT-17 was similar extent to that by codeine. Anti-electroshock effect was half as potent as that of phenobarbital. The inhibitory effect on the transportation of intestinal contents in mice was far weaker than that of codeine. Effect on the respiratory and circulatory systems were also investigated.

    Topics: Analgesia; Animals; Antitussive Agents; Blood Pressure; Bronchi; Cats; Codeine; Dextromethorphan; Dogs; Female; Guinea Pigs; In Vitro Techniques; Intestines; Lethal Dose 50; Male; Mice; Morphinans; Muscle Contraction; Muscle Tonus; Rabbits; Respiration; Seizures; Sleep; Trachea; Vasomotor System

1976