dextromethorphan and Epilepsy

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

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

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

To evaluate the impact of sodium benzoate and dextromethorphan treatment on patients with the attenuated form of nonketotic hyperglycinemia.. Families were recruited with 2 siblings both affected with attenuated nonketotic hyperglycinemia. Genetic mutations were expressed to identify residual activity. The outcome on developmental progress and seizures was compared between the first child diagnosed and treated late with the second child diagnosed at birth and treated aggressively from the newborn period using dextromethorphan and benzoate at dosing sufficient to normalize plasma glycine levels. Both siblings were evaluated with similar standardized neurodevelopmental measures.. In each sibling set, the second sibling treated from the neonatal period achieved earlier and more developmental milestones, and had a higher developmental quotient. In 3 of the 4 sibling pairs, the younger sibling had no seizures whereas the first child had a seizure disorder. The adaptive behavior subdomains of socialization and daily living skills improved more than motor skills and communication.. Early treatment with dextromethorphan and sodium benzoate sufficient to normalize plasma glycine levels is effective at improving outcome if used in children with attenuated disease with mutations providing residual activity and when started from the neonatal period.

Topics: Child; Child Development; Child, Preschool; Colorado; Delayed Diagnosis; Dextromethorphan; Early Diagnosis; Epilepsy; Excitatory Amino Acid Antagonists; Female; Humans; Hyperglycinemia, Nonketotic; Infant; Infant, Newborn; Intelligence Tests; Male; Neuropsychological Tests; Siblings; Sodium Benzoate; Time-to-Treatment

Dextromethorphan (DXM) has unique toxicity that may be difficult to diagnose. We present a case of a young woman who presented to our emergency department (ED) initially diagnosed with recurrent seizures. Paramedics brought a 19-year-old woman to the ED. Witnesses noted "shaking," which the patient did not recall. The patient denied fever, antecedent trauma, or neurological complaint. She was recently administered lamotrigine for bipolar disorder. She was a former alcoholic with no history of developing withdrawal. She admitted to marijuana use but denied use of any other illicit substances. Her vital signs and physical examination were unremarkable. She had a normal brain computed tomography, electrocardiogram, and laboratory evaluation. There was no alcohol detected. Her urine drug screen was negative for opiates, benzodiazepines, cocaine, amphetamines, barbiturates, phencyclidine, and tricyclic antidepressants. She was diagnosed with new-onset seizure and discharged home. No abnormalities were seen in the brain magnetic resonance imaging scan and electroencephalogram. She was scheduled for a cardiac syncope workup, but never followed through. Two months later, she presented to the hospital again for a similar complaint. Coworkers reported witnessing sudden tonic-clonic movements and confusion. On ED presentation, the patient was tachycardic with a heart rate of 110 beats/min and had horizontal nystagmus. She was alert with a flat affect. She did not recall events but answered questions appropriately. Repeat radiographic and laboratory evaluations were normal including urine drug screen and computed tomography. Upon questioning, she admitted to abusing DXM for the past several months. A serum DXM level at this time was 988.3 ng/mL. She was admitted to the hospital for 24 hours without sequelae. All further diagnostic testing was cancelled, and she was referred to a drug rehabilitation program. Abuse of DXM is increasing in incidence. The serum level of our patient was almost 10-fold greater than the reported therapeutic level. The toxicity of DXM is unique, and abuse should be considered in all patients presenting to the ED with new-onset seizure. Dextromethorphan abuse should be considered in young adults who present with previously undiagnosed seizure activity.

Topics: Antitussive Agents; Dextromethorphan; Diagnosis, Differential; Electrocardiography; Epilepsy; Female; Follow-Up Studies; Humans; Recurrence; Sorption Detoxification; Substance-Related Disorders; Tomography, X-Ray Computed; Young Adult

The objective of this study was to investigate the effects of three low-affinity NMDA receptor antagonists, MRZ 2/279 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl), AR-R 15896AR ([+]-alpha-phenyl-2-pyridine-ethanamine diHCl) and dextromethorphan on epileptiform activity in vitro. Epileptiform discharges were elicited in DBA/2 mouse cortical slices by perfusion with Mg(2+)-free artificial cerebrospinal fluid. MRZ 2/279, AR-R 15896AR and dextromethorphan all reversibly decreased the frequency of the discharges in a concentration-dependent manner. The IC(50)'s for MRZ 2/279, AR-R 15896AR and dextromethorphan were 5.2, 10.8 and 55.9 microM, respectively. These low-affinity NMDA receptor antagonists may be proved to be clinically effective with fewer adverse effects than drugs with high-affinity for the NMDA receptor-operated channel.

Topics: Animals; Cerebral Cortex; Cyclopentanes; Dextromethorphan; Electric Conductivity; Electrophysiology; Epilepsy; Excitatory Amino Acid Antagonists; Female; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Pyridines; Receptors, N-Methyl-D-Aspartate

Carbamazepine (CBZ) is widely used in the treatment of epilepsy. The drug is principally metabolized by CYPs to 10, 11-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsant properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be implicated in CBZ biotransformation. Our purpose was to establish an experimental model to determine the interaction of CBZ with other antiepileptic drugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. We used liver microsomes from rabbit treated with various compounds known to induce principally some CYPs subfamilies. Having tested all the compounds we demonstrated that only the animals treated with CYP3A inducers were able to metabolize CBZ strongly. The CBZ biotransformation was inhibited by anti CYP3A antibodies. All the CYP3A subfamily substrates specifically decrease CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subfamily is primarily involved in CBZ metabolism. Using this model we investigated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, primidone, progabide, vigabatrin and lamotrigine.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Anticonvulsants; Aryl Hydrocarbon Hydroxylases; Biotransformation; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dextromethorphan; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Enzyme Inhibitors; Epilepsy; Hypnotics and Sedatives; In Vitro Techniques; Male; Microsomes, Liver; Nifedipine; Protein Isoforms; Rabbits

The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo.. Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6 beta-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stripentol and carbamazepine.. In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 mumol/L, whereas the corresponding in vitro value was 80 mumol/L.. Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Topics: Adult; Anticonvulsants; Caffeine; Carbon Dioxide; Carbon Isotopes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dextromethorphan; Dioxolanes; Epilepsy; Humans; Hydrocortisone; In Vitro Techniques; Mixed Function Oxygenases; Reference Values; Time Factors

Topics: Anticonvulsants; Child, Preschool; Coenzymes; Dextromethorphan; Epilepsy; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; N-Methylaspartate; Pteridines

High doses of dextromethorphan (20-42 mg/kg/day) were given to four critically ill children with seizures and frequent epileptiform abnormalities in the EEG that were refractory to antiepileptic drugs. Their acute diseases (hypoxia, head trauma and hypoxia, neurodegenerative disease, hypoglycaemia) were thought to be due in part to N-methyl-D-aspartate (NMDA) receptor mediated processes. Treatment with dextromethorphan, an NMDA receptor antagonist, was started between 48 hours and 14 days after the critical incident. In three patients the EEG improved considerably within 48 hours and seizures ceased within 72 hours. In the patient with neurodegenerative disease the effect on the EEG was impressive, but the seizures were not controlled. Despite the improvement of the EEG the clinical outcome was poor in all children: three died in the critical period or due to the progressing disease; the patient with hypoglycaemia survived with severe neurological sequelae. Plasma concentrations of dextromethorphan varied between 74-1730 ng/ml and its metabolite dextrorphan varied between 349-3790 ng/ml. In one patient corresponding concentrations in CSF were lower than those in plasma. The suppression of epileptic discharges by the doses of dextromethorphan given suggests that such doses are sufficient to block NMDA receptors.

Topics: Adolescent; Brain Diseases; Child, Preschool; Dextromethorphan; Electroencephalography; Epilepsy; Epilepsy, Post-Traumatic; Female; Humans; Infant; Male; Receptors, N-Methyl-D-Aspartate

Some non-competitive antagonists of N-methyl-D-aspartate (NMDA) were evaluated for potency to antagonize audiogenic seizures in genetically epilepsy-prone rats, following intraperitoneal administration. Phencyclidine (PCP), dizocilpine (MK-801), ketamine, ifenprodil and dextromethorphan, displayed anticonvulsant activity at doses similar to those which impaired performance in the rotarod equilibrium procedure. The noncompetitive NMDA receptor antagonists, at doses which slightly overlapped with the doses required for a full anticonvulsant protection against audiogenic seizures in genetically epilepsy-prone rats, induced profound untoward behavioural effects. This behavioural syndrome was characterized by marked ataxia, hyperactivity, stereotypes and wet dog shakes. In contrast, the effective anticonvulsant dose of 3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) was less than that required to impair rotarod performance and did not produce the PCP-like syndrome. A potential use in antiepileptic therapy, of CPPene or other new selective NMDA antagonists, with fewer neurotoxic effects but not for non-competitive antagonists such as MK-801, is suggested.

Topics: Acoustic Stimulation; Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Dextromethorphan; Dizocilpine Maleate; Epilepsy; Injections, Intraperitoneal; Ketamine; Male; Movement; Phencyclidine; Piperazines; Piperidines; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Three commonly used antitussive compounds were tested for their ability to block epileptiform activity recorded extracellularly from hippocampal and olfactory cortex slices maintained in vitro. Antitussives were bath-applied to brain slices either before or after epileptiform activity was induced. Dextromethorphan (DM) prevented electrically evoked epileptiform afterdischarges and arrested spontaneous bursting induced by exposure to added NMDA or to Mg2(+)-free medium. In contrast, caramiphen (CM) and carbetapentane (CB) were effective against epileptiform activity induced by Mg2(+)-free medium, but not by NMDA. Atropine was not effective in blocking epileptiform activity at concentrations 10 times the effective concentration of CM, which has known cholinolytic activity. Our results suggest that all these antitussives exert their anticonvulsant action at the DM binding site. Neither cholinolytic activity nor antagonism of the NMDA receptor-channel complex appears to be necessary for antitussives to prevent or arrest epileptiform activity. DM appears to have a separate NMDA-antagonist property in addition to its actions at the DM site. Our neurophysiological evidence supports the hypothesis that these antitussives have anticonvulsant properties independent of any action at the NMDA receptor-channel complex.

Topics: Animals; Antitussive Agents; Cyclopentanes; Dextromethorphan; Electric Stimulation; Epilepsy; Evoked Potentials; Guinea Pigs; Hippocampus; In Vitro Techniques; Magnesium; N-Methylaspartate; Olfactory Bulb

Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.

Topics: Animals; Aspartic Acid; Carbachol; Cerebral Cortex; Dextromethorphan; Dose-Response Relationship, Drug; Epilepsy; In Vitro Techniques; Levorphanol; N-Methylaspartate; Potassium Channels; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma