sodium-oxybate and Seizures

1,4-butanediol (1,4-BD) is an industrial solvent that is metabolized to gamma-hydroxybutyrate (GHB), a gamma-aminobutyric acid agonist and central nervous system depressant. GHB and its analogues are popular drugs of abuse. Withdrawal from these agents is characterized by autonomic instability and altered mental status. We report a case of withdrawal from 1,4-BD lasting 6 days and complicated by new onset of seizures and rhabdomyolysis. In addition, we conducted a systematic review of the English literature pertaining to withdrawal from GHB, 1,4-BD and gamma-butyrolactone (GBL). Data collected from source articles included last use prior to symptom onset, clinical features on presentation, duration of symptoms and outcome. Twenty-seven studies with 57 episodes of withdrawal were included. Thirty-six cases (63%) involved GHB, 3 cases (5%) involved 1,4-BD and 18 (32%) involved GBL. The most common patient symptoms were tremor (67%), hallucinations (63%), tachycardia (63%) and insomnia (58%). Seizures and rhabdomyolysis each occurred in 7% of cases, but only 1 death occurred. Emergency physicians must consider withdrawal from these agents when patients present with clinical features suggestive of a sedative-hypnotic withdrawal syndrome.

Topics: 4-Butyrolactone; Adult; Butylene Glycols; Humans; Illicit Drugs; Male; Rhabdomyolysis; Seizures; Sodium Oxybate; Substance Withdrawal Syndrome

gamma-Hydroxybutyrate (GHB) is a GABA-active CNS depressant, commonly used as a drug of abuse. In the early 1990s, the US Drug Enforcement Administration (DEA) warned against the use of GHB and restricted its sale. This diminished availability of GHB caused a shift toward GHB analogues such as gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) as precursors and surrogates. Both GBL and 1,4-BD are metabolically converted to GHB. Furthermore, GBL is commonly used as a starting material for chemical conversion to GHB. As such, the clinical presentation and management of GBL and 1,4-BD intoxication shares a great deal of common ground with that for GHB. This similarity exists not only for acute intoxication but also for withdrawal in those patients with a history of extended high-dose abuse. This review examines the history of GHB analogue abuse as well as the clinical presentation and management of acute intoxication and withdrawal associated with abuse of these compounds.

Topics: 4-Butyrolactone; Body Temperature Regulation; Butylene Glycols; GABA Modulators; Humans; Illicit Drugs; Seizures; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders

GHB, GBL, and 1,4-BD are prevalent drugs of abuse in the United States. Unfortunately, attempts to regulate GHB have been circumvented by clandestine trafficking through the Internet and marketing of "natural" chemical precursors . Despite repeated FDA warnings to the public about their dangers as well as recent federal scheduling of GHB and GBL, they remain accessible as "club drugs" on Internet websites, as natural dietary supplements in health food stores, and as illicit products manufactured at home or in clandestine laboratories. EDs and poison control centers nationwide will undoubtedly continue to manage GHB, GBL, and 1,4-BD toxicities.

Topics: 4-Butyrolactone; Adjuvants, Anesthesia; Adolescent; Butylene Glycols; Emergency Medical Services; Female; Humans; Lorazepam; Seizures; Sodium Oxybate; Structure-Activity Relationship; Substance-Related Disorders; Treatment Outcome

Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAA or GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity.

Topics: 4-Butyrolactone; Animals; Central Nervous System; Convulsants; Electroencephalography; GABA Agonists; gamma-Aminobutyric Acid; Humans; Mammals; Muscle Contraction; Picrotoxin; Rabbits; Rats; Receptors, GABA; Respiration; Seizures; Sodium Oxybate

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation.. Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements.. Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Topics: Amino Acid Metabolism, Inborn Errors; Aminobutyrates; Child; Developmental Disabilities; Epilepsy; gamma-Aminobutyric Acid; Humans; Seizures; Sodium Oxybate

In the current study the link among the γ-hydroxybutyrate (GHB)/pentylenetetrazole (PTZ)-induced absence-like seizures and concomitant decreases in the core temperature, as well as electroencephalographic (EEG) activity during rewarming from deep hypothermia produced by a drug-free protocol were investigated. During the rewarming period after deep cooling, most Wistar rats suffered from bilaterally synchronous spike and waves with no or mild behavioral correlates. Spike and wave seizures were temperature-dependent and were initially registered when body temperature (Tb) reached 25-27°C, but mostly during the mild hypothermia of 0.3-1.3°C (Tb of 36.3-37.3°C). In chemical absence models, spike and wave discharges were also closely accompanied by mild systemic hypothermia, as both PTZ- and GHB-induced temperature decreases ranged from about 1-1.4°C respectively, together with EEG markers of absence activity. Thus, throughout the different experimental designs, the occurrence of spike and wave discharges was always related to a mild (0.3-1.4°C) decrease of Tb. Benzodiazepine diazepam as the GABAA-positive allosteric modulator and CGP 62349 as the selective antagonist of GABAB receptors were used to determine if their well-known anticonvulsant properties also affect hypothermia elicited by these drugs. Finally, during the course of spontaneous rewarming from deep hypothermia, another selective GABAB-blocking agent, CGP 35348, was used to elucidate if GABAB inhibitory system could be critically implicated in the generation of hypothermia-dependent spike and waves. Diazepam prevented both the PTZ-induced hypothermia and electrographic absence seizures, but these two beneficial effects did not occur in the GHB model. Even though diazepam delayed GHB-induced maximal temperature decrease, the GHB effects remained highly significant. The GABAB antagonist CGP 62349 completely prevented hypothermia as well as absence seizures in both chemical models. Likewise, spike and wave discharges, registered during the spontaneous rewarming from deep hypothermia, were completely prevented by CGP 35348. These findings show that systemic hypothermia should definitely be regarded as a marker of GABAB receptor activation. Moreover, the results of this study clearly show that initial mild temperature decrease should be considered as strong absence-provoking factor. Hypothermia-induced nonconvulsive seizures also highlight the importance of continuous EEG monitoring in children underg

Topics: Animals; Anticonvulsants; Benzoates; Body Temperature Regulation; Cerebral Cortex; Diazepam; Epilepsy, Absence; Hypothermia; Male; Organophosphorus Compounds; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, GABA-B; Seizures; Sodium Oxybate

The U.S. Consumer Product Safety Commission announced a recall of Aqua Dots (Spin Master Ltd.; Toronto, Canada) on November 7, 2007 due to children becoming ill after swallowing beads from these toy craft kits. Reports suggested that the beads contained 1,4-butanediol (1,4-BD), a precursor to gamma-hydroxybutyrate (GHB), rather than the intended, but more expensive 1,5-pentanediol (1,5-PD). We measured the 1,4-BD and 1,5-PD content of Aqua Dots beads to determine if 1,5-PD had been completely substituted with 1,4-BD by the manufacturer, and if the reported clinical effects from swallowing Aqua Dots beads were consistent with the estimated ingested 1,4-BD dose.. In vitro bench research using gas chromatography-mass spectroscopy (GC-MS) was performed. Dilute samples of pure 1,4-BD and 1,5-PD in water were used for the calibration of the GC-MS instrument. We then soaked Aqua Dots beads in water for varying durations, and the resultant solutions were analyzed for 1,4-BD and 1,5-PD content.. Aqua Dots beads weighed 79.3 mg each (+/- 0.6 mg, SD), and contained 13.7% (+/- 2.4%, SD) 1,4-BD by weight; this corresponds to a 1,4-BD content of 10.8 mg (+/- 1.9 mg, SD) per bead. No 1,5-PD was detected in any beads.. Aqua Dots beads contained a surprisingly high amount (nearly 14%) of extractable 1,4-BD. No 1,5-PD was detected, corroborating reports that this chemical had been completely replaced with a substitute that is metabolized into GHB after ingestion. Reports of ataxia, vomiting, seizure activity, and self-limited coma in children are consistent with the ingestion of several dozen Aqua Dots beads.

Topics: Ataxia; Butylene Glycols; Calibration; Child; Coma; Consumer Product Safety; Gas Chromatography-Mass Spectrometry; Glycols; Humans; Pentanes; Play and Playthings; Seizures; Sodium Oxybate; Solubility; Vomiting

Succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disorder of gamma-aminobutyric acid degradation. While neurological manifestations, such as developmental delay, are typical during infancy, limited data are available on adolescent and adult symptomatology.. We overview the phenotype of 33 adolescents and adults (10.1-39.5 years of age, mean: 17.1 years, 48% females) with SSADH deficiency. For this purpose, we applied a database with systematic questionnaire-based follow-up data.. Sixty-six percent of patients (n=21) presented by 6 months of age, 14% from 6-12 months of age, 5% from 1-2 years of age, and 14% from 2-4 years of age, mean age at first symptoms was 11+/-12 months. However, mean age at diagnosis was 6.6+/-6.4 years of age. Presenting symptoms encompassed motor delay, hypotonia, speech delay, autistic features, seizures, and ataxia. Eighty-two percent demonstrated behavioral problems, such as attention deficit, hyperactivity, anxiety, or aggression, and 33% had >or=3 behavior problems. Electroencephalograms showed background slowing or epileptiform discharges in 40% of patients. Treatment approaches are then summarized.. The variable phenotype in SSADH deficiency suggests the likelihood that this disease may be under-diagnosed. Families of patients with SSADH deficiency should be counseled and supported regarding the anticipated persistence of various neuropsychiatric symptoms into adulthood.

Topics: Adolescent; Adult; Amino Acid Metabolism, Inborn Errors; Ataxia; Behavioral Symptoms; Child; Child, Preschool; Cohort Studies; Developmental Disabilities; Electroencephalography; Female; Follow-Up Studies; gamma-Aminobutyric Acid; Humans; Intellectual Disability; Language Development Disorders; Male; Seizures; Sleep Wake Disorders; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Surveys and Questionnaires

A 2-year-old boy and a 10-year-old girl presented to the emergency department with a decreased level of consciousness. The girl had had persistent vomiting and a seizure. Urine metabolic screening tests were positive for gamma-hydroxybutyrate (GHB). Samples from toy beads ingested by both children contained 1,4-butanediol, which is metabolised to GHB in humans. Regulatory authorities were notified, leading to an international recall of the toy beads.

Topics: Australia; Butylene Glycols; Child; Child, Preschool; Consumer Product Safety; Emergency Service, Hospital; Female; Humans; Hypnotics and Sedatives; Male; Play and Playthings; Seizures; Sodium Oxybate; Unconsciousness

Riluzole, an anti-amyotrophic lateral sclerosis drug, known to decrease presynaptic glutamate release, is viewed as a candidate supplementary medication for epilepsy. In the present study, we compared the effects of riluzole and valproate (VPA) in the pilocarpine-induced limbic seizure model and in the gamma-hydroxybutyrate lactone (GBL)-induced absence seizure model. We applied immunohistochemical study for vesicular transporter 1 (VGLUT1) and extracellular recording in the rat dentate gyrus of both pilocarpine- and GBL-induced seizure models to measure effects of riluzole and VPA. Both VPA and riluzole treatments reduced VGLUT1 immunoreactivity. Riluzole treatment completely inhibited pre-ictal spikes and spike-wave discharges in the pilocarpine- and GBL-induced epilepsy models, whereas VPA partially inhibited these phenomena. In both seizure models, the anti-epileptic effects of VPA and riluzole are basically related to anti-glutamatergic (reducing field excitatory postsynaptic potential slope and excitability ratio), not GABAergic (paired-pulse inhibition) effect. Riluzole was more effective at reducing seizure activity in both epilepsy models than VPA. These results suggest that riluzole is a potential antiepileptic drug with activity against limbic seizure and absence seizure.

Topics: Animals; Anticonvulsants; Dentate Gyrus; Disease Models, Animal; Epilepsy, Absence; Excitatory Postsynaptic Potentials; Limbic System; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Riluzole; Seizures; Sodium Oxybate; Status Epilepticus; Valproic Acid; Vesicular Glutamate Transport Protein 1

Physostigmine is an acetylcholinesterase inhibitor and can produce fasciculations, seizures, bradycardia, and asystole. gamma-hydroxybutyrate (GHB) increases acetylcholine levels in the central nervous system and can decrease heart rate. Despite this, physostigmine has been proposed as an arousal agent to treat coma from overdoses of GHB. The authors hypothesized that in the setting of severe GHB intoxication, physostigmine would reverse sedation without producing adverse effects such as a decrease in heart rate, seizures, and fasciculations.. GHB intoxication was induced in 20 rats by intraperitoneal injection of 700 mg/kg of the GHB precursor gamma-butyrolactone. One hour later, rats were randomly assigned to receive either physostigmine (0.06 mg/kg) intraperitoneally or an equivalent volume of saline. After administration of physostigmine, rats were continuously monitored by a blinded observer for arousal (return of righting reflex), fasciculations, and seizures. Heart rate and respiratory rate were recorded at 0, 5, 15, and 60 minutes after administration of physostigmine. Data were analyzed using repeated-measures analysis of variance and chi-square test. A pretest sample size calculation determined that 10 rats per group would detect a change in arousal from 0% to 50% and a 10% change in heart rate.. No rats in either group had arousal within one hour (p = 1.0); however, ten of ten physostigmine-treated rats developed signs of physostigmine toxicity (fasciculations, 7; seizures, 3), while no controls developed signs of physostigmine toxicity (p = 0.00). The authors were unable to detect a decrease in heart rate.. Physostigmine did not produce a 50% change in arousal as measured by a return of righting reflex but did produce physostigmine toxicity (fasciculations and seizures) in this rat model of severe GHB intoxication.

Topics: Animals; Arousal; Cholinesterase Inhibitors; Coma; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Overdose; Fasciculation; Heart Rate; Male; Physostigmine; Random Allocation; Rats; Rats, Sprague-Dawley; Reflex; Respiratory Mechanics; Seizures; Sodium Oxybate

Gamma-hydroxybutyrate and its metabolic precursors gamma butyrolactone and 1,4-butanediol are widely used recreational drugs known to cause short periods of deep sedation with rapid recovery. We present a case of survival with good neurological outcome following massive ingestion in which the patient remained sedated for 14 h.

Topics: Adult; Butylene Glycols; Female; Humans; Illicit Drugs; Respiratory Insufficiency; Seizures; Sodium Oxybate

Topics: Age Factors; Bradycardia; Humans; Hypotension; Middle Aged; Seizures; Sodium Oxybate; Substance-Related Disorders

Experimental absence seizures are associated with perturbations in the presynaptic release of GABA and glutamate within thalamocortical circuitry. The release of both glutamate and GABA is regulated by group III metabotropic glutamate receptors (mGluRs). Therefore, we examined the susceptibility of mice lacking the mGluR4 subtype of mGluR (mGluR4(-/-)) versus their wild-type controls (mGluR4(+/+)) to absence seizures induced either by gamma-hydroxybutyrate (GHB) or the GABA(B) agonist (-) baclofen or by low doses of the GABA(A) receptor (GABA(A)R) antagonists pentylenetetrazole, bicuculline, or picrotoxin. There was no difference between mGluR4(-/-) and mGluR4(+/+) mice in threshold to absence seizures induced by either GHB or (-) baclofen. In contrast, the mGluR4(-/-) mice were markedly resistant to absence seizures induced by low doses of GABA(A)R antagonists. No differences were observed between mGluR4(-/-) and mGluR4(+/+) mice in threshold to clonic or tonic seizures induced by higher doses of GABA(A)R antagonists, strychnine, or electroshock, indicating that seizure resistance in the mGluR4(-/-) mice was restricted solely to absence seizures. The resistance of mGluR4(-/-) mice to absence seizures induced by GABA(A)R antagonists was mimicked by bilateral administration of a mGluR4 antagonist into the nucleus reticularis thalami (nRT) of mGluR4(+/+) mice. Conversely, intra-nRT administration of a mGluR4 agonist in mGluR4(+/+) mice exacerbated GABA(A)R-induced absence seizures. These data indicate that the presence of mGluR4 within nRT is critical to GABAergic modulation of thalamocortical synchronization in normal and pathological states, such as generalized absence epilepsy.

Topics: Animals; Baclofen; Cerebral Cortex; Convulsants; Epilepsy, Absence; Excitatory Amino Acid Antagonists; GABA Antagonists; GABA-A Receptor Antagonists; Mice; Mice, Knockout; Neural Pathways; Receptors, GABA-A; Receptors, Metabotropic Glutamate; Seizures; Sodium Oxybate; Thalamus

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-phenylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity assays. The most potent anticonvulsant compounds were alpha-(benzylamino)-gamma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzylamide (4) with median effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively. alpha-(4-Phenylpiperazinyl)-gamma-hydroxybutyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (18) were also tested for their ability to potentiate [3H]-muscimol binding and to inhibit [35S]-TBPS binding (as indices of GABA-A receptor potentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is mediated. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3-9) were also evaluated for their ability to displace [3H]-nitrendipine from voltage-sensitive calcium channel (VSCC) receptors isolated from rat cortex.

Topics: Animals; Anticonvulsants; Calcium Channels; Cell Membrane; Electroshock; Male; Mice; Prosencephalon; Rats; Receptors, GABA-A; Seizures; Sodium Oxybate; Structure-Activity Relationship

Gamma hydroxy butyrate (GHB) is a central nervous system depressant approved as an anaesthetic in some countries; however, with the exception of investigational research, it is not approved for any use in the United States. Primary groups using GHB include party and nightclub attendees and bodybuilders. In addition, GHB is one of several agents characterized as a "date rape" drug. During August 1995-September 1996, poison control centers in New York and Texas received reports of 69 acute poisonings and one death attributed to ingestion of GHB. This report describes two cases and summarizes the investigations of GHB use in Texas and New York. The findings of these investigations underscore the health hazards associated with use of GHB.

Topics: Adolescent; Adult; Central Nervous System Depressants; Coma; Fatal Outcome; Female; Heart Arrest; Humans; Male; New York; Respiratory Insufficiency; Seizures; Sodium Oxybate; Substance-Related Disorders; Texas

Topics: Adolescent; Adult; Central Nervous System Depressants; Coma; Fatal Outcome; Female; Heart Arrest; Humans; Male; New York; Respiratory Insufficiency; Seizures; Sodium Oxybate; Substance-Related Disorders; Texas

Topics: Coma; Emergency Service, Hospital; Fatal Outcome; Humans; Seizures; Sodium Oxybate

Topics: 3,4-Methylenedioxyamphetamine; Designer Drugs; Diagnosis, Differential; Humans; Seizures; Sodium Oxybate; Substance-Related Disorders; Unconsciousness

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals. GHB has been hypothesized to induce this effect via the postsynaptic gamma-aminobutyric acidB (GABAB) receptor. We sought to test this hypothesis by examining the affinity of GABAB agonists and antagonists for the [3H]GHB binding site, the affinity of GHB and a GHB antagonist for the [3H]GABAB binding site, and the effect of guanine nucleotides and pertussis toxin on both, using autoradiographic binding assays. GHB and its antagonist, NCS 382, did not compete for [3H]GABAB binding, nor did (-)-baclofen or the [3H]GABAB antagonists, CGP 35348 or SCH 50911, compete for [3H]GHB binding; however, the GABAB agonist 3-amino-propylphosphinic acid (3-APPA), and the GABAB antagonists phaclofen and 2-hydroxysaclofen (2-OH saclofen) did show a weak affinity for [3H]GHB binding in frontal cortex. GTP and the nonhydrolyzable GTP analogues, GTP gamma S and Gpp(NH)p, depressed [3H]GABAB binding throughout the brain, but increased [3H]GHB binding in frontal cortex and thalamus, those regions involved in GHB-induced absence seizures. Pertussis toxin significantly depressed [3H]GABAB binding throughout the brain, but attenuated [3H]GHB binding only in frontal cortex, and to a lesser degree than [3H]GABAB binding. The guanine nucleotide-induced changes in [3H]GHB and [3H]GABAB binding were due to a change in KD for both. Moreover, GTP gamma S reversed the ability of 3-APPA, phaclofen, and 2-OH saclofen to compete for [3H]GHB binding. These data do not support the hypothesis that GHB acts through the postsynaptic GABAB receptor to produce absence seizures. Rather, they raise the possibility either that the [3H]GHB binding site may be an isoform of the presynaptic GABAB receptor or that an independent GHB site is operative in the GHB model of absence seizures.

Topics: Animals; Autoradiography; Baclofen; Benzocycloheptenes; Binding Sites; Brain; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Guanosine Triphosphate; In Vitro Techniques; Male; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Seizures; Sodium Oxybate; Stereoisomerism

Topics: 4-Aminobutyrate Transaminase; Aldehyde Oxidoreductases; Brain Diseases, Metabolic; GABA Antagonists; gamma-Aminobutyric Acid; Humans; Metabolism, Inborn Errors; Seizures; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Treatment Outcome; Vigabatrin

Gamma hydroxybutyrate (GHB) is an illicitly marketed substance promoted by body builders as a growth hormone releaser. Poisoning can produce seizures and coma. Acute poisonings from GHB have primarily been reported on the West coast and the Southeast. We report two cases from Kansas City where the patients presented in, or developed profound coma. Physicians should suspect GHB poisoning in patients who present with unexplained seizures and/or coma, particularly if they are body builders, health food fanatics or dieters.

Topics: Acute Disease; Adult; Alcohol Drinking; Coma; Diet Fads; Female; Humans; Male; Missouri; Seizures; Sodium Oxybate; Weight Lifting

Topics: 4-Butyrolactone; Animals; Cerebral Cortex; Corpus Callosum; Electroencephalography; Epilepsy, Absence; Epilepsy, Generalized; Ethosuximide; Evoked Potentials; Injections, Intraperitoneal; Male; Phenytoin; Rats; Rats, Wistar; Seizures; Sodium Oxybate; Valproic Acid

Gamma-hydroxybutyrate (GHB) was intracortically applied in two doses (first 10 and then 20 mg/ml) to awake Wistar rats using microdialysis. Simultaneously, EEG and the release of somatostatin-like immunoreactivity (SLI) were measured from the frontal cortex. Intracerebrally administered GHB induced cortical epileptogenic spikes, but not high voltage spindles (HVS) as reported after systemic administration, and seizures with myoclonic jerks and contraversive head movements. Compared to the basal level, GHB (10 mg/ml) initially increased the release of SLI (p < 0.05). However, when the frequency of spikes and seizures rose rapidly (p < 0.001), SLI release decreased significantly (p < 0.001). Minimum release of SLI occurred when seizures were most frequent (during perfusion with 20 mg/ml GHB), while after removal of the drug it rose above the basal level (p < 0.05). According to these results, intracortically applied GHB increases the release of SLI in the surrounding tissue. However, further exposure of GHB leads to a manifestation of epileptic spikes and seizures, during which the release of SLI is significantly attenuated. This suggests that release of somatostatin is affected during epileptic phenomena induced also by intracortical GHB application.

Topics: Animals; Cerebral Cortex; Dialysis; Electroencephalography; Male; Rats; Rats, Wistar; Reference Values; Seizures; Sodium Oxybate; Somatostatin

We report a series of 5 representative patients in California who experienced adverse reactions from the illicitly marketed substance gamma-hydroxybutyrate (GHB). The drug is a putative neurotransmitter marketed as a growth hormone releaser for bodybuilders. The most commonly reported symptoms included abrupt drowsiness, dizziness, and a "high". Other effects were headache, nausea, vomiting, myoclonic jerking, and short-term coma. There have been no reported deaths. If product use is discontinued, full recovery with no long-term side effects is universal. No clear dose-response effect was observed; this may be attributable to differences in susceptibility, wide variations in doses taken by the same person, or the coingestion of other substances. Case interviews confirm that, despite being banned by the US Food and Drug Administration, GHB is still widely available in the underground drug market. Athletes and bodybuilders may take drugs for which there are claims of improved performance or body image. Physicians should be alert for signs of GHB poisoning in emergency department and clinic patients.

Topics: Adult; Aged; California; Drug Interactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Seizures; Sensation; Sleep Stages; Sodium Oxybate

Topics: Central Nervous System Diseases; Gastrointestinal Diseases; Humans; Quackery; Seizures; Sodium Oxybate

gamma-Hydroxybutyric acid (GHB) produces a constellation of EEG and behavioral changes when given to animals, which represent an experimental model of generalized absence seizures. gamma-Butyrolactone (GBL), the prodrug of GHB, produces these changes more rapidly and consistently than GHB, such that the rat treated with GBL is a more reproducible and predictable model of absence seizures. The hypothesis that the epileptogenic effects of GBL are due solely to its conversion to GHB was tested. The regional concentration of both compounds in brain was determined in time-course and dose-response studies, as well as at the onset of EEG changes, induced by both GHB and GBL. Also, the EEG and behavioral effects of both drugs were ascertained after intrathalamic injection in the rat. gamma-Butyrolactone produced a rapid onset of bilaterally synchronous spike and wave discharges in the rat, which correlated with a rapid appearance of GHB in brain in the GBL-treated animals. In the GHB-treated animals, EEG changes occurred 20 min after administration of GHB when levels of GHB in the brain were peaking. The threshold concentration of GHB in brain for EEG changes, in both GHB-and GBL-treated animals was 240 x 10(-6) M. The concentration of GBL in brain peaked 1 min after administration of GBL and fell rapidly to undetectable levels within 5 min. Bilateral injection of GHB into thalamus resulted in a brief burst of spike and wave discharges, while GBL, administered into the thalamus, had no effect. The use of GBL as a prodrug for GHB in this model of generalized absence seizures is valid, since GBL itself was inactive.

Topics: 4-Butyrolactone; Animals; Brain; Brain Chemistry; Dose-Response Relationship, Drug; Electrodes; Electroencephalography; Epilepsy; Gas Chromatography-Mass Spectrometry; Injections, Intraperitoneal; Male; Rats; Rats, Inbred Strains; Seizures; Sodium Oxybate

Sixteen cases of adverse effects due to a new health-food product, gamma-hydroxybutyrate (GHB), were reported to the San Francisco Bay Area Regional Poison Control Center in the 5-month period from June to October 1990. Cases have also been reported in eight other states. Adverse effects included coma (four patients) and tonic-clonic seizurelike activity (two patients). Doses ranged from 1/4 teaspoon to 4 tablespoons. Acute symptoms resolved within 7 hours. GHB was investigated as an anesthetic agent during the 1960s until seizures and lack of analgesia precluded its use. It was recently introduced in the health-food market as a food supplement for body builders with claims of anabolic effects by stimulating growth hormone release. GHB remains under investigational new drug status with the Food and Drug Administration and is illegal for over the counter sale. The Food and Drug Branch of the California Department of Health Services has prohibited further sale of this product in California as have health departments in Florida and South Carolina; however, new cases continue to be reported. Health professionals should be aware of the potential health hazards of GHB.

Topics: Adolescent; Adult; Coma; Diet Fads; Female; Humans; Male; Middle Aged; Seizures; Sodium Oxybate; Substance-Related Disorders

The effect of the unsaturated lactone, gamma-crotonolactone (GCL), against spike wave discharges (SWD) in two pharmacological models of generalized absence seizures in rat was investigated. The models used were the gamma-hydroxybutyrate (GHB) model and the low dose pentylenetetrazole model. GCL pretreatment resulted in a significant decrease in duration of SWD in both models. In addition, this compound reduced the ability of the agonist, muscimol, to enhance SWD duration in the GHB model and was effective in developing animals as well as in adult animals with GHB-induced SWD. These data suggest that GCL may be a useful tool in the study of basic mechanisms of SWD generation in experimental absence seizures.

Topics: 4-Butyrolactone; Animals; Anticonvulsants; Disease Models, Animal; Electroencephalography; Furans; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Sodium Oxybate; Time Factors

A child presenting with mild psychomotor retardation, hypotonia, microcephaly and hyperkinesis is described. Urinary organic acid analysis by combined gas chromatography-mass spectrometry revealed 4-hydroxybutyric aciduria. Succinic semialdehyde dehydrogenase activity in extracts of white cells derived from the patient was less than 10% of control values.

Topics: Ataxia; Child; Female; Humans; Hydroxybutyrates; Hyperkinesis; Intellectual Disability; Muscle Hypotonia; Seizures; Sodium Oxybate

The electroencephalographic (EEG) response of 6-hydroxydopamine (6-OHDA)-treated and control rats to gamma-butyrolactone (GBL) the prodrug of gamma-hydroxybutyrate (GHB), was determined. Neonatal treatment with 6-OHDA produced a significant reduction of noradrenaline in cortex and hippocampus while sparing noradrenaline in the hypothalamus. Brain dopamine was unaffected. The electrographic seizure produced by GBL was significantly prolonged and more severe in the 6-OHDA-treated animals. That portion of the hypersynchronous seizure induced by GBL which is pharmacologically sensitive to antipetit mal anticonvulsants, Stage 1, was however shortened in the 6-OHDA-treated animals. Reduction of forebrain noradrenaline seems to have a complex effect on GBL-induced seizure in that it results in a reduction of hypersynchronous EEG activity but in a prolongation of the more severe EEG changes of burst suppression normally seen with higher doses of GBL.

Topics: Animals; Brain Chemistry; Electroencephalography; Electrophysiology; Hydroxybutyrates; Hydroxydopamines; Male; Norepinephrine; Oxidopamine; Rats; Seizures; Sodium Oxybate

Topics: Anesthesia Recovery Period; Anesthesia, General; Asphyxia; Child, Preschool; Female; Humans; Hydroxybutyrates; Ketamine; Male; Seizures; Sodium Oxybate

Topics: 4-Butyrolactone; Amygdala; Anesthetics; Animals; Central Nervous System; Electroencephalography; Hydroxybutyrates; Ketamine; Male; Pentylenetetrazole; Phencyclidine; Rats; Seizures; Sodium Oxybate

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Bicuculline; Dose-Response Relationship, Drug; Drug Synergism; Hydroxybutyrates; Male; Mice; Muscimol; Oxazoles; Pentylenetetrazole; Seizures; Sodium Oxybate; Strychnine; Sulfhydryl Compounds

Topics: Adult; Age Factors; Cerebral Ventricles; Child, Preschool; Humans; Hydroxybutyrates; Infant; Lumbosacral Region; Middle Aged; Seizures; Sodium Oxybate; Specimen Handling

A well-known protective effect of aminooxyacetic acid against thiosemicarbazide convulsions was confirmed; it was shown that a similar, although somewhat weaker activity, was exerted by sodium hydroxybutyrate. Surprisingly, the effect of aminooxyacetic acid was diminished by sodium hydroxybutyrate. Sodium hydroxybutyrate in combination with aminooxyacetic acid decreased the protective activity of the latter against thiosemicarbazide convulsions and diminished the extent of GABA accumulation characteristic of aminooxyacetic acid action. This effect is attributed to the competition between the aminooxyacetic acid, sodium hydroxybutyrate and GABA for alpha-ketoglutarate-GABA-transaminase and possible for the GABA-ergic receptor.

Topics: Acetates; Aminooxyacetic Acid; Animals; Anticonvulsants; Brain; gamma-Aminobutyric Acid; Hydroxybutyrates; Mice; Seizures; Semicarbazides; Sodium Oxybate

Topics: Cats; Electroencephalography; Hearing; Hydroxybutyrates; Pharmacology; Research; Seizures; Sodium Oxybate; Touch; Toxicology

The actions of sodium 4-hydroxybutyrate, gamma-aminobutyric acid and meprobamate have been studied in unanaesthetized animals, in local anaesthetic tests, on isolated organ preparations, on convulsions induced by picrotoxin and strychnine, and on monosynaptic (patellar) and polysynaptic (plantar) reflexes of the spinal cord. Sodium 4-hydroxybutyrate induced a sleep-like state with three unusual features: the righting reflex was remarkably persistent, respiration was good throughout and recovery was abrupt. gamma-Aminobutyric acid was inactive and meprobamate caused flaccid paralysis with loss of the righting reflex. None of the agents affected the responses of the rat diaphragm either to direct stimulation of the muscle or to indirect stimulation through the phrenic nerve. Only meprobamate reduced the responses of theguinea-pig isolated ileum preparation, showed local anaesthetic action and had an anticonvulsant action. All three compounds were capable, after intravenous or topical application, of blocking plantar reflexes in doses which did not affect the patellar reflex. The spinal animal responded in the same way, to the same dose of sodium 4-hydroxybutyrate, as the decerebrate preparation. Topical application to the motor cortex had no effect on spinal reflexes. We conclude that sodium 4-hydroxybutyrate acts preferentially on the internuncial neurones in the spinal cord but differs from meprobamate in its other actions. The similarity between the actions of sodium 4-hydroxybutyrate and of gamma-aminobutyric acid provides furtherevidence in support of the hypothesis that sodium 4-hydroxybutyrate is involved in the gamma-aminobutyric acid metabolic pathways.

Topics: Aminobutyrates; Anesthesia; Anesthesia, Local; Anesthesiology; Animals; Blood Pressure Determination; Cats; Diaphragm; gamma-Aminobutyric Acid; Hydroxybutyrates; Injections, Intraperitoneal; Injections, Intravenous; Meprobamate; Mice; Nervous System Physiological Phenomena; Neuromuscular Junction; Pharmacology; Phrenic Nerve; Picrotoxin; Poultry; Rats; Reflex; Research; Seizures; Sodium; Sodium Oxybate; Spinal Cord; Strychnine; Swine; Toxicology

Topics: Animals; Butyrates; Hyperoxia; Mice; Oxygen; Seizures; Sodium; Sodium Oxybate