sodium-oxybate and 1-4-butanediol

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) "Butandiol 1,4" (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.

Topics: Body Fluids; Butylene Glycols; Ethanol; Humans; Male; Middle Aged; Sodium Oxybate

γ-hydroxybutyrate (GHB) is synthesized endogenously from γ-aminobutyric acid (GABA) or exogenously from 1,4-butanediol (butane-1,4-diol; 1,4-BD) or γ-butyrolactone (GBL). GBL, and 1,4-BD are rapidly converted to GHB. The gastric absorption time, volume of distribution, and half-life of GHB are between 5 and 45 min, 0.49 ± 0.9 L/kg, and between 20 and 60 min, respectively. GHB and its analogues have a dose-dependent effect on the activation of GHB receptor, GABA-B, and GABA localized to the central nervous system. After ingestion, most patients present transient neurological disorders (lethal dose: 60 mg/kg). Chronic GHB consumption is associated with disorders of use and a withdrawal syndrome when the consumption is discontinued. GHB, GBL, and 1,4-BD are classified as narcotics but only the use of GHB is controlled internationally. They are used for drug facilitated (sexual) assault, recreational purposes, slamsex, and chemsex. To confirm an exogenous intake or administration of GHB, GBL, or 1-4-BD, the pre-analytical conservation is crucial. The antemortem cutoff doses for detection are 5 and 5-15 mg/L, with detection windows of 6 and 10 h in the blood and urine, respectively Control of GHB is essential to limit the number of users, abuse, associated risks, and death related to their consumption.

Topics: 4-Butyrolactone; gamma-Aminobutyric Acid; Humans; Sodium Oxybate; Substance Withdrawal Syndrome

Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, and a medical treatment for narcolepsy and other neuropsychiatric disorders. Its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are endogenously converted to GHB and thereby exert their psychobehavioural effects. In humans, GHB has a wide spectrum of properties ranging from stimulation and euphoria in lower doses, to sedation, deep sleep, and coma after ingestion of high doses. However, behavioural studies in healthy volunteers remain scarce and are usually limited to psychomotor performance testing. Most available data arise from either qualitative studies with illicit users or clinical trials examining therapeutic properties of GHB (then usually termed sodium oxybate). Here, we present an overview of the behavioural effects of GHB, GBL, and 1,4-BD in these three populations. GHB and its precursors strongly influence behaviours related to core human autonomic functions such as control of food intake, sexual behaviour, and sleep-wake regulation. These effects are instrumentalised by illicit users and clinically utilised in neuropsychiatric disorders such as narcolepsy, fibromyalgia, and binge-eating syndrome. Considering the industry withdrawal from psychopharmacology development, repurposing of drugs according to their behavioural and clinical profiles has gained increasing relevance. As such, GHB seems to be an attractive candidate as an experimental therapeutic in depression.

Topics: 4-Butyrolactone; Animals; Butylene Glycols; Central Nervous System Depressants; Circadian Rhythm; Eating; Humans; Sexual Behavior; Social Behavior; Sodium Oxybate; Substance Withdrawal Syndrome

Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4-butanediol (1,4-BD) use extracted from the UK's National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%); young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0-6500; SD 758)mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption.

Topics: 4-Butyrolactone; Butylene Glycols; Female; Humans; Male; Sodium Oxybate; Substance-Related Disorders; United Kingdom

Topics: Alkaloids; Anesthetics, Dissociative; Anesthetics, Intravenous; Butylene Glycols; Central Nervous System Stimulants; Humans; Illicit Drugs; Ketamine; Primary Health Care; Referral and Consultation; Sodium Oxybate; Substance-Related Disorders

Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal.. OVID MEDLINE and ISI Web of Science databases were searched using the terms "GHB," "gamma-hydroxybutyrate," "gamma-hydroxybutyric acid," "4-hydroxybutanoic acid," "sodium oxybate," "gamma-butyrolactone," "GBL," "1,4-butanediol," and "1,4-BD" alone and in combination with the keywords "pharmacokinetics," "kinetics," "poisoning," "poison," "toxicity," "ingestion," "adverse effects," "overdose," and "intoxication." In addition, bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches produced 2059 nonduplicate citations of which 219 were considered relevant.. There is limited information regarding statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over this timeframe.. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affinity for GHB-receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a partial GABA(b) receptor agonist and indirectly through its metabolism to form GABA.. GHB is rapidly absorbed by the oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly distributed across the blood-brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20-60 minute half-life. The majority of a dose is eliminated completely within 4-8 hours. The related chemicals, 1,4-butanediol and gamma butyrolactone, are metabolized endogenously to GHB. CLINICAL FEATURES OF POISONING: GHB produces CNS and respiratory depression of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia. Fatalities have been reported. MANAGEMENT OF POISONING: Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory depression. Gastrointestinal decontamination is unlikely to be beneficial. Pharmacological intervention is rarely required for bradycardia; however, atropine administration may occasionally be warranted. WITHDRAWAL SYNDROME: Abstinence after chronic use may result in a withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options.. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening, though treatment with benzodiazepines is usually effective.

Topics: 4-Butyrolactone; Antidotes; Butylene Glycols; Charcoal; Humans; Sodium Oxybate; Substance Withdrawal Syndrome; Therapeutic Irrigation; Tissue Distribution

The chronic abuse of Gamma-Hydroxybutyrate (GHB) as a designer drug as well as it's physiological precursors Gamma-Butyrolactone (GBL) and 1,4-Butandiole (1,4-BD) confronts child and adolescent psychiatrists with new challenges. The acute withdrawal of GHB with its cardiovascular and delirant symptoms is of particular importance for child and adolescent psychiatrists.. In the present paper theoretical and biological aspects of acute GHB-/GBL-/1,4-BD-withdrawal syndrome are presented, and selected cases are discussed as regards potential treatment.. High dose treatment with benzodiazepines was successful in some cases of acute GHB-/GBL-/1,4-BD-withdrawal syndrome. Complications were severe dystonia under neuroleptic treatment, and also side-effects of treatment with benzodiazepines. Further problems were vegetative symptoms, electrocardiographic changes, rhabdomyolysis, acute renal failure, and death.. Acute GHB-withdrawal syndrome is a life-threatening condition which requires immediate intensive care treatment along with continuous monitoring of vital parameters. As acute GHB-withdrawal syndrome can present with symptoms close to psychotic episodes or acute alcohol withdrawal this condition is relevant for child and adolescent psychiatrists.

Topics: 4-Butyrolactone; Acute Disease; Adolescent; Anesthetics, Intravenous; Antipsychotic Agents; Benzodiazepines; Butylene Glycols; Child; Critical Care; Delusions; Diagnosis, Differential; Drug Interactions; Humans; Psychoses, Substance-Induced; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders

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

Laboratory detection of gamma-hydroxybutyrate (GHB) has been published as early as the 1960s. However, wide-scale use of GHB during the 1990s has led to the development of current analytic methods to test for GHB and related compounds. Detection of GHB and related compounds can be clinically useful in confirming the cause of coma in an overdose patient, determining its potential role in a postmortem victim, as well as evaluating its use in a drug-facilitated sexual assault victim. Analytical method sensitivity must be known in order to determine the usefulness and clinical application. Most laboratory cut-off levels are based on instrument sensitivity and will not establish endogenous versus exogenous GHB levels. Interpretation of GHB levels must include a knowledge base of endogenous GHB, metabolism of GHB and related compounds, as well as postmortem generation. Due to potential analytical limitations in various GHB methods, it is clinically relevant to specifically request for GHB as well as related GHB compounds if they are also in question. Various storage conditions (collection time, types of containers, use of preservatives, storage temperature) can also affect the analysis and interpretation of GHB and related compounds.

Topics: 4-Butyrolactone; Butylene Glycols; Chemical Phenomena; Chemistry, Physical; Chromatography, Gas; GABA Modulators; Gas Chromatography-Mass Spectrometry; Humans; Illicit Drugs; Sodium Oxybate; Substance Abuse Detection

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

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO.

Topics: Adult; Alcohol Dehydrogenase; Butylene Glycols; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Enzyme Inhibitors; Fomepizole; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Psychotropic Drugs; Sodium Oxybate; Solvents; Treatment Outcome

1,4-Butanediol (BD) is converted to gamma-hydroxybutyrate (GHB) after ingestion, and is associated with cases of dependence, coma, and death. The pharmacology of BD after oral ingestion has not been described in humans. Eight healthy volunteers (five men) were administered 25 mg/kg BD in a single oral dose after an overnight fast in a double-blinded, placebo-controlled, crossover study. Vital signs were monitored, and serial blood samples collected over 24 h for gas chromatography-mass spectrometry analysis of BD and GHB levels. Subjective mood and symptoms responses were assessed by visual analog scale. All subjects completed the study without significant adverse effects. BD was quickly absorbed and cleared, with time to maximal plasma concentration of 24+/-12 min, and elimination half-life (T(1/2)) of 39.3+/-11 min. BD was extensively converted to GHB, with a mean maximum GHB concentration of 45.6+/-19.7 mg/l reached 39.4+/-11.2 min after BD ingestion. GHB T(1/2) averaged 32.3+/-6.6 min. Some subjects exhibited slow oral clearance of BD, which tended to correlate with a variant haplotype of the alcohol dehydrogenase gene ADH-IB G143A. Mean CL/F was 151.5+/-176.5 ml/min kg for four subjects with variant haplotype versus 598.8+/-446.6 ml/min kg for four wild-type subjects (P=0.061). Subjects reported feeling less awake and alert, less able to concentrate, and more lightheaded in the first 90 min after BD ingestion. Pulse oximetry readings were lower 45 min after BD dosing with a mean oxygen saturation of 98.5% with BD versus 99.6% with placebo (P=0.031). Transient increases in mean systolic and diastolic blood pressure were observed, but other vital signs remained unchanged. BD was extensively converted to GHB after oral administration, but significant inter-individual variability in the rate of metabolism, possibly related to variants in ADH-IB, was observed. At the modest dose studied, significant clinical effects were not seen.

Topics: Administration, Oral; Adult; Alcohol Dehydrogenase; Area Under Curve; Blood Pressure; Butylene Glycols; Cross-Over Studies; Double-Blind Method; Female; Gas Chromatography-Mass Spectrometry; Half-Life; Haplotypes; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oximetry; Oxygen; Pharmacology, Clinical; Sodium Oxybate; Time Factors

Topics: Accelerated Idioventricular Rhythm; Butylene Glycols; Electrocardiography; Humans; Male; Middle Aged; Sodium Oxybate

We report a case of fatal intoxication from 1,4-butanediol (1,4-BD), which was ingested by a young and "naïve" gamma-hydroxybutyrate (GHB) consumer during a party with the co-ingestion of alcohol, cannabis, and methylene-dioxy-methamphetamine. The following drug concentrations were found using gas chromatography coupled with mass spectrometry on autopsy samples and on a cup and a glass found at the scene: 20,350 mg/L (bottle) for 1,4-BD; 1020 mg/L (femoral blood), 3380 mg/L (cardiac blood), 47,280 mg/L (gastric content), and 570 mg/L (vitreous humor) for GHB. The concentration of GHB is difficult to interpret in forensic cases due to the possibility of an endogenous production of GHB. The variable tolerance of the user may also modify the peri- and postmortem GHB concentrations. This case underscores the need to have many different sources of toxicology samples analyzed to avoid the hypothesis of endogenous production of GHB.

Topics: Adult; Butylene Glycols; Central Nervous System Depressants; Dronabinol; Drug Overdose; Ethanol; Gas Chromatography-Mass Spectrometry; Gastrointestinal Contents; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Sodium Oxybate; Vitreous Body

1,4-Butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) pro-drug, with multiple commercial uses, and a drug of abuse. Although there are case reports of a withdrawal syndrome following 1,4-BD use, no studies have evaluated the physical dependence potential of 1,4-BD and characterized the time course of withdrawal.. Vehicle and then 1,4-BD were administered continuously 24 h/day via intragastric catheters in male baboons (Papio anubis, n=3). Dosing was initiated at 100 mg/kg and increased by 100mg/kg/day to 400mg/kg. After a stabilization period, doses of 500 and then 600 mg/kg/day were each maintained for 3-4 weeks. Plasma levels of 1,4-BD and GHB were determined for each dose condition. Physical dependence was assessed via administration of a GABA-B antagonist (precipitated withdrawal test) during administration of the 600 mg/kg dose and via abrupt termination of chronic 1,4-BD administration (spontaneous withdrawal test). Outcome measures included the number of food pellets earned, performance on a fine-motor task, observed behaviors, and plasma levels of GHB and 1,4-BD.. Following maintenance of 1,4-BD 600 mg/kg for 3 weeks, the number of food pellets earned was significantly decreased. At the end of chronic 1,4-BD dosing, the levels of GHB in plasma ranged from 1290 to 2300 μmol/L and levels of 1,4-BD in plasma ranged from 13.1 to 37.9 μmol/L. Signs of physical dependence were observed following precipitated and spontaneous withdrawal tests. Seizures were not observed.. These data indicate chronic 1,4-BD produced physical dependence in baboons and the withdrawal syndrome can be characterized as mild to intermediate.

Topics: Animals; Butylene Glycols; Conditioning, Operant; Infusions, Parenteral; Male; Papio anubis; Prodrugs; Severity of Illness Index; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs.

Topics: 4-Butyrolactone; Animals; Area Under Curve; Butylene Glycols; Catalepsy; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Sodium Oxybate; Toxicity Tests, Acute; Toxicity Tests, Chronic

The demand of high throughput methods for the determination of gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butane-diol (1,4BD) as well as for pregabalin is increasing. Here we present two analytical methods using ultra-high pressure liquid chromatography (UPLC) and tandem mass spectrometric (MS/MS) detection for the determination of GHB, beta-hydroxybutyrate (BHB), pregabalin, 1,4BD and GBL in whole blood and urine. Using the 96-well formate, the whole blood method is a simple high-throughput method suitable for screening of large sample amounts. With an easy sample preparation for urine including only dilution and filtration of the sample, the method is suitable for fast screening of urine samples. Both methods showed acceptable linearity, acceptable limits of detection, and limits of quantification. The within-day and between-day precisions of all analytes were lower than 10% RSD. The analytes were extracted from matrices with recoveries near 100%, and no major matrix effects were observed. Both methods have been used as routine screening analyses of whole blood and urine samples since January 2010.

Topics: 3-Hydroxybutyric Acid; 4-Butyrolactone; Butylene Glycols; Chromatography, High Pressure Liquid; gamma-Aminobutyric Acid; Humans; Illicit Drugs; Pregabalin; Reproducibility of Results; Sensitivity and Specificity; Sodium Oxybate; Tandem Mass Spectrometry

A liquid-chromatography-tandem-mass-spectrometry method using pneumatically assisted electrospray ionisation (LC-ESI-MS/MS) was developed for the simultaneous determination of γ-hydroxybutyric acid (GHB), γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in human ante-mortem and post-mortem whole blood. The blood proteins were precipitated using a mixture of methanol and acetonitrile, and the extract was cleaned-up by passage through a polymeric strong cation exchange sorbent. Separation of the analytes and their structural isomers was obtained using a column with a zwitterionic stationary phase. Matrix-matched calibrants, combined with isotope dilution, were used for quantitative analysis. GHB was determined in both positive and negative ion modes. The relative intra-laboratory reproducibility standard deviations were better than 10% and 6% for blood samples at concentrations of 2 mg/L and 20-150 mg/L, respectively. The mean true extraction recoveries were 80% for GHB and greater than 90% for GBL and 1,4-BD at concentration levels of 20-50 mg/L. The limits of detection were approximately 0.5 mg/L for GHB and GBL, and 0.02 mg/L for 1,4-BD in ante-mortem blood. The corresponding lower limits of quantification were less than 1 mg/L for GHB and GBL, and less than 0.1 mg/L for 1,4-BD. GBL was unstable in whole blood freshly preserved with a sodium fluoride oxalate mixture, but the stability could be improved significantly by preservation with a sodium fluoride citrate EDTA mixture.

Topics: 4-Butyrolactone; Butylene Glycols; Central Nervous System Depressants; Chromatography, Liquid; Citrates; Drug Stability; Fixatives; Forensic Toxicology; Humans; Limit of Detection; Oxalates; Reproducibility of Results; Sodium Fluoride; Sodium Oxybate; Solid Phase Extraction; Specimen Handling; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

A method capable of quantifying endogenous concentrations of gamma-hydroxybutyrate (GHB) in human head hair was developed and validated using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). Hair was digested under alkaline conditions, and GHB was isolated using liquid-liquid extraction. LC/MS/MS was performed using atmospheric pressure chemical ionization in the negative mode, multiple reaction monitoring, and deuterated internal standard (GHB-D(6)). Linearity was observed between 0.1 and 100 ng/mg GHB (R(2) = 1.000). The limits of detection and quantitation in human hair were 0.2 and 0.4 ng/mg, respectively. Accuracy at 2 ng/mg and 10 ng/mg was determined to be 97% and 94%, and intra-assay CVs at these concentrations were 5.2% and 7.4% (n = 4). Beta-hydroxybutyrate (BHB), alpha-hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol did not produce an interference, and there was negligible ion suppression or enhancement from the matrix.

Topics: 3-Hydroxybutyric Acid; 4-Butyrolactone; Butylene Glycols; Chromatography, Liquid; Forensic Toxicology; Hair; Humans; Sodium Oxybate; Tandem Mass Spectrometry

Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are prodrugs for gamma-hydroxybutyrate (GHB). Like GHB, GBL and 1,4-BD are drugs of abuse, but their behavioral effects may differ from GHB under some conditions.. The first study compared the behavioral effects of GBL (32-240 mg/kg) and 1,4-BD (32-240 mg/kg) with each other and to effects previously reported for GHB (32-420 mg/kg). A second study determined GHB pharmacokinetics following intragastric administration of GHB, GBL, and 1,4-BD.. Operant responding for food, observed behavioral effects, and a fine-motor task occurred at multiple time intervals after administration of drug or vehicle. In a separate pharmacokinetics study, blood samples were collected across multiple time points after administration of GHB, GBL, and 1,4-BD.. Like GHB, GBL, and 1,4-BD impaired performance on the fine-motor task, but the onset of motor impairment differed across drugs. GBL and 1,4-BD dose dependently decreased the number of food pellets earned, but at lower doses than previously observed for GHB. Similar to GHB, both GBL and 1,4-BD produced sedation, muscle relaxation, gastrointestinal symptoms, and tremors/jerks. Administration of GBL and 1,4-BD produced higher maximum concentrations of GHB with shorter times to maximum concentrations of GHB in plasma when compared to GHB administration.. GBL and 1,4-BD produced behavioral effects similar to those previously reported with GHB and the time course of effects were related to blood levels of GHB. Given their higher potency and faster onset of effects, the abuse liability of GBL and 1,4-BD may be greater than GHB.

Topics: 4-Butyrolactone; Animals; Area Under Curve; Behavior, Animal; Butylene Glycols; Conditioning, Operant; Dose-Response Relationship, Drug; Food; GABA Modulators; Male; Motor Skills; Papio; Prodrugs; Reward; Sodium Oxybate; Substance-Related Disorders

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

Ingestion of plastic toys is common in children and usually does not result in harm. We report a case of coma in a 20-month-old child after an ingestion of a toy containing 1,4-butanediol, an industrial solvent used to manufacture plastics. When ingested, 1,4-butanediol is metabolized to gamma-hydroxybutyrate, which can have significant systemic effects including death. Health care providers should suspect the possibility of a toxic component when a presumed nontoxic object causes unusual symptoms.

Topics: Butylene Glycols; Coma; Diagnosis, Differential; Eating; Follow-Up Studies; Foreign Bodies; Humans; Infant; Male; Oropharynx; Play and Playthings; Prodrugs; Sodium Oxybate; Suction

Gamma-hydroxybutyrate (GHB) and its metabolic precursor, 1,4-butanediol (BDL), are widely used recreational drugs. Although most commonly described as CNS depressants, GHB and BDL elicit significant sympathomimetic cardiovascular responses [increases in mean arterial pressure (MAP) and heart rate] when administered parenterally. Given that humans most commonly ingest both drugs orally, we examined the dose-response relationships for intragastrically administered GHB and BDL on MAP and heart rate in conscious rats using radiotelemetry. The intragastric administration of GHB increased MAP. BDL increased both MAP and heart rate and was approximately 10-fold more potent as a cardiovascular stimulant than GHB when administered intragastrically. Pretreatment with ethanol prevented the lethality of BDL. These data indicate that 1) both GHB and BDL produce cardiovascular responses when administered intragastrically and 2) BDL is more potent and potentially more dangerous than GHB when administered via this route.

Topics: Animals; Blood Pressure; Butylene Glycols; Drug Administration Routes; Heart Rate; Rats; Rats, Sprague-Dawley; Sodium Oxybate

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

The purpose of the present study was to provide further information about the effects of gamma-hydroxybutyrate (GHB) on memory. Initially, the acute effects of gamma-butyrolactone (GBL, 75-200 mg/kg IP), 1,4-butanediol (1,4-BD, 100-300 mg/kg IP), and ethanol (1.0-3.0 g/kg, oral), as well as GHB (100-300 mg/kg IP), were examined in rats responding under a delayed-matching-to-position (DMTP) procedure with delays from 0 to 32 s. Acute administration of all four drugs reduced the number of trials completed and also reduced accuracy during delay trials, but not during trials without a delay. Some tolerance developed to the disruptive effects of GHB following exposure to 300 mg/kg/day for 29 consecutive days. These data indicate that GHB can disrupt working memory and speed of responding, and that tolerance can develop to these effects. Moreover, the acute effects of GHB under the DMTP procedure resemble those of its metabolic precursors, GBL and 1,4-BD, and of the prototypical CNS depressant drug, ethanol.

Topics: Anesthetics, Intravenous; Animals; Butylene Glycols; Central Nervous System Depressants; Conditioning, Operant; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Tolerance; Ethanol; Male; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is used as a recreational drug, with significant associated morbidity and mortality; it is therefore a class C drug under the Misuse of Drugs Act (1971). However, its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD) remain legally available despite having similar clinical effects.. The aim of this study was to determine whether the relative proportions of self-reported ingestions of GHB or its precursors GBL and 1,4BD were similar to those seen in analysis of seized drugs.. Retrospective review of our clinical toxicology database to identify all cases of self-reported recreational GHB, GBL and 1,4BD use associated with ED presentation in 2006. Additionally all seized substances on people attending local club venues were analysed by a Home Office approved laboratory to identify any illicit substances present.. In 2006, there were a total of 158 ED presentations, of which 150 (94.9%) and 8 (5.1%) were GHB and GBL self-reported ingestions respectively; 96.8% (153) were recreational use. Of the 418 samples seized, 225 (53.8%) were in liquid form; 85 (37.8%) contained GHB and 140 (62.2%) contained GBL. None of the seized samples contained 1,4BD and there were no self-reported 1,4BD ingestions.. Self-reported GHB ingestion was much more common than GBL ingestion, whereas GBL was more commonly found in the seized samples. These differences suggest that GBL use may be more common than previously thought and we suggest that there should be further debate about the legal status of the precursors of GHB.

Topics: 4-Butyrolactone; Adult; Aged; Butylene Glycols; Emergency Medical Services; Female; Humans; Illicit Drugs; Length of Stay; Male; Middle Aged; Retrospective Studies; Sodium Oxybate; Substance-Related Disorders

GHB is a drug of abuse and acute poisonings have been an increasing medical problem over the last decade in Sweden.. To document all cases of GHB poisonings in Gothenburg during 1995-2004 and to record drug-related deaths to compare the toxicity of GHB with other illicit drugs, such as heroin and amphetamine.. The number of GHB-poisoned patients treated at the Sahlgrenska University Hospital has been recorded with the help of an in-house database. The number of deaths by illicit drugs was recorded during 2004. Seizures of the drugs GHB, 1,4-butanediol, and GBL were registered between 1996 and 2004.. The number of poisoned patients was 259. The number of seizures with GHB was 743, GBL 343, and 1,4-butanediol 236. In 2004 the number of deaths was 6 with heroin, 7 with GHB, 32 with amphetamine, 6 with cocaine, and one with methadone. One patient with GHB poisoning died during hospital care.. Intoxication by GHB has substantial morbidity and abuse of GHB has substantial mortality. The acute prognosis is good but long-term prognosis is insecure with an increased risk for drug dependency and an early death.

Topics: 4-Butyrolactone; Adolescent; Adult; Anesthetics, Intravenous; Butylene Glycols; Cause of Death; Female; Forensic Medicine; Humans; Illicit Drugs; Male; Police; Sodium Oxybate; Substance Abuse Detection; Substance-Related Disorders; Sweden

Anecdotal reports indicate that GHB produces subjective effects similar to those of ethanol. However, recent investigations comparing the discriminative stimulus effects of GHB to those of ethanol suggest that the subjective effects of these substances may differ considerably. To explore further potential differences between GHB and ethanol, 16 male Sprague-Dawley rats were trained in a three-lever drug discrimination procedure to discriminate ethanol (1.0 g/kg, experiment 1; 1.5 g/kg, experiment 2) and GHB (300 mg/kg) from vehicle. Dose-response functions determined with both training compounds revealed a clear dissociation between the discriminative stimulus effects of these drugs. As expected, the GHB precursors gamma-butyrolactone and 1,4-butanediol produced full substitution for GHB. In addition, the GABA(B) receptor agonist baclofen substituted for GHB, whereas the benzodiazepine flunitrazepam and the NMDA receptor antagonist ketamine engendered greater responding on the ethanol-lever. GHB's discriminative stimulus effects were blocked by the GABA(B) receptor antagonist CGP-35348 but only partially blocked by the putative GHB receptor antagonist NCS 382. These findings are consistent with previous reports of GHB's discriminative stimulus effects in two-choice drug discrimination procedures and provide additional evidence that these effects are distinct from those of ethanol.

Topics: 4-Butyrolactone; Animals; Baclofen; Benzocycloheptenes; Butylene Glycols; Discrimination, Psychological; Ethanol; Flunitrazepam; GABA Agonists; GABA Antagonists; GABA Modulators; Ketamine; Male; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Sodium Oxybate

1,4-Butanediol (BD), a substance of abuse, is bioactivated to gamma-hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcohol dehydrogenase, we hypothesized that there may also be a metabolic interaction between ethanol (ETOH) and BD. We therefore studied, in rats, the plasma PK of GHB, BD and ETOH each at two intravenous (IV) doses, when each substance was given alone, and when GHB or BD was co-administered with ETOH. Results showed that bioconversion of intravenously administered BD to GHB was complete, and that both GHB and BD exhibited nonlinear PK. Various population PK models were analyzed using NONMEM VI, and the best disposition model was found to include two PK compartments each for BD, an (unmeasured) putative semialdehyde intermediate (ALD), GHB and ETOH, the presence of nonlinear (Michaelis-Menten) elimination for each compound, and several mutual inhibition processes. The most prominent mutual metabolic inhibition was found between ETOH and BD, while that between GHB and ETOH was not significant. In vitro studies using liver homogenates confirmed mutual metabolic inhibitions between GHB and BD. Oral absorption of BD was best described by a first-order process with lag-time and pre-systemic metabolism from BD to ALD. Oral absorption of BD (as BD plus ALD) was rapid and complete. The fraction of the absorbed dose entering the central compartment as BD was 30% for the 1.58 mmol/kg dose and 55% for the 6.34 mmol/kg dose. At 6.34 mmol/kg IV, the onset of loss of righting reflex (LRR) for BD was significantly delayed vs. that produced by GHB (72.0 +/- 9.1 min vs. 6.7 +/- 0.6 min, respectively, p < 0.001), and the total duration of LRR was prolonged for BD vs. GHB (192 +/- 28 min vs. 117 +/- 2 min, respectively, p < 0.05). Relative to IV dosing, oral BD produced similar but more variable LRR effects. These results may provide a quantitative PK framework for the understanding of the toxicokinetics and toxicodynamics of both BD and GHB.

Topics: Administration, Oral; Animals; Biological Availability; Butylene Glycols; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Male; Rats; Rats, Sprague-Dawley; Sodium Oxybate

To develop a classroom activity that applied pertinent pharmaceutical concepts to examine the use and limitations of a commercially available test drink coaster in detecting the presence of a date-rape drug, sodium gamma-hydroxybutyrate (NaGHB), in beverages.. An activity exercise involving a combination of self-study, hands on participation, and classroom discussion was developed. Topics incorporated into the activity were drug-assisted rape, the concepts of false positives and negatives, and prodrug and pH chemistry.. Based on questionnaires completed by the students, the intended concepts were reinforced and students demonstrated an increased awareness of the potential shortcomings of the commercial test devices. The activity was well received by the majority of students.. The developed activity stimulated student awareness and interest in several principles relevant in pharmaceutical education, including drug-assisted rape, consumer-based drug testing of NaGHB, and the chemical basis for its limitations. The activity requires no special equipment other than the drink coasters and can be easily completed in one 2-hour classroom session.

Topics: 4-Butyrolactone; Acid-Base Equilibrium; Adolescent; Adult; Anesthetics, Intravenous; Beverages; Butylene Glycols; Education, Pharmacy; Female; Humans; Male; Prodrugs; Reagent Strips; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is an increasingly popular drug of abuse that causes stimulation, euphoria, anxiolysis or hypnosis, depending on the dose used. Low doses of the drug are used recreationally, and also implicated in drug-facilitated sexual assaults. Because of the unusually steep dose-response curves, accidental GHB overdosing, leading to coma, seizures or death can occur. Being a controlled substance, GHB is often substituted with its non-scheduled precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD), which are rapidly metabolized into GHB in the body. Here we describe an assay for GHB, GBL and BD in blood and/or urine samples. GHB and BD were extracted from diluted 200 microL aliquots of samples with t-butylmethylether (plus internal standard benzyl alcohol) in test tubes preloaded with NaCl. After acidification and centrifugation the solvent phase was transferred to a test tube preloaded with Na(2)SO(4), incubated for 30 min, centrifuged again, and evaporated in vacuum. The residue was mixed with N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) in acetonitrile, and injected into a GC-MS. When analyzing GBL, the salting-out step was omitted, and analysis was performed with a GC-FID apparatus. As revealed by the validation data this procedure is suitable for quantitative determination of GHB and its precursors in blood and/or urine samples.

Topics: 4-Butyrolactone; Analytic Sample Preparation Methods; Butylene Glycols; Central Nervous System Depressants; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Humans; Reproducibility of Results; Sodium Chloride; Sodium Oxybate; Spectrometry, Mass, Electrospray Ionization; Substance Abuse Detection

The production of the terpolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxybutyrate), P(3HB-co-3HV-co-4HB), by Alcaligenes sp. A-04 was investigated to determine the superior biodegradable polymer properties over those of poly(3-hydroxybutyrate), P(3HB), and its copolymers. The highest terpolymer content of 68% (w/w) was produced by Alcaligenes sp. A-04 at 60 h by shake-flask cultivation. The terpolymer with 93 mol% 4HB mole fraction units was produced when the cultivation time was extended to 96 h. Moreover, it was found that Alcaligenes sp. A-04 could utilize 1,4-butanediol for the synthesis of 3HB and 4HB monomers as well as the sodium salt of 4-hydroxybutyrate. The terpolymer content was 30% (w/w) and the composition was P(33%3HB-co-16%3HV-co-51%4HB). Next, terpolymers with 4HB mole fraction units ranging from 50 to 90 mol% were produced by varying the medium composition and cultivation time. The thermal and mechanical properties of the resulting terpolymers were different from those of the copolymers with a similar mole fraction of monomer units. The terpolymer P(4%3HB-co-3%3HV-co-93%4HB) showed an elongation of 430%, a toughness of 33 MPa, and Young's modulus of 127 MPa similar to those of low-density polyethylene. The terpolymer P(11%3HB-co-34%3HV-co-55%4HB) showed Young's Modulus of 618 MPa similar to that of polypropylene.

Topics: Alcaligenes; Biodegradation, Environmental; Butylene Glycols; Fructose; Industrial Microbiology; Pentanoic Acids; Polyesters; Sodium Oxybate

Pigeons trained to discriminate 0.1 mg/kg flumazenil, proposed as an in-vivo model to study interactions with diazepam-insensitive gamma-aminobutyric acid (GABA)A receptors, were tested with various GABAergic and non-GABAergic compounds. As a result of its pharmacological selectivity, the model was suitable for further examining previously reported flumazenil-like effects of gamma-hydroxybutyrate (GHB). Flumazenil and the GABAA negative modulator Ro 15-4513 produced 82-100% flumazenil-appropriate responding. Diazepam and the direct-acting GABAA agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) produced 38-64% flumazenil-appropriate responding. GHB, its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), and the GABAB agonists baclofen and SKF97541 produced 0-24% flumazenil-appropriate responding. Baclofen shifted the flumazenil dose-response curve to the right and down, possibly involving perceptual masking of the discriminative stimulus effects of flumazenil by agonist activity at GABAB receptors. These masking effects of baclofen were blocked by the GABAB antagonist CGP35348. When CGP35348 was given together with GHB to block its GABAB agonist effects, GHB did not produce flumazenil-appropriate responding. Conceivably, effects of GHB at non-GABAB receptors (e.g. diazepam-sensitive GABAA receptors and GHB receptors) may interfere with the expression of its flumazenil-like discriminative stimulus effects. The asymmetric substitution between GHB and flumazenil is consistent with the hypothesis that the discriminative stimulus effects of GHB consist of several components, not all of which are mimicked by flumazenil.

Topics: 4-Butyrolactone; Animals; Baclofen; Benzocycloheptenes; Butylene Glycols; Columbidae; Discrimination, Psychological; Dose-Response Relationship, Drug; Flumazenil; GABA Agonists; GABA Antagonists; GABA Modulators; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Organophosphorus Compounds; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally worldwide. Since the scheduling of GHB by the USA and the United Nations in 2000-2001, the recreational use of GHB precursors has reportedly increased. The aim of this study was to examine if potency differences of GHB and GHB-like compounds are due to their blood-brain barrier permeability. The effects of peripheral and central administration of GHB, GHB precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), and the gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on schedule-controlled responding were examined in rats. GHB and baclofen were 276- and 253-fold more potent, respectively, after intracerebroventricular (i.c.v.) administration than after intraperitoneal (i.p.) administration, whereas GBL and 1,4-BD, up to a dose of 1780 microg were without effect after i.c.v. administration. These data suggest that GBL and 1,4-BD are not metabolically converted to GHB in the brain, that enhanced brain penetration cannot account for potency differences between compounds, and that baclofen, like GHB, can readily cross the blood-brain barrier.

Topics: 4-Butyrolactone; Anesthetics, Intravenous; Animals; Baclofen; Behavior, Animal; Blood-Brain Barrier; Brain; Butylene Glycols; GABA Agonists; Injections, Intraperitoneal; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Sodium Oxybate

To quantify gamma-hydroxybutyrate (GHB) and its physiological metabolites, gamma-aminobutyric acid (GABA), 1,4-butanediol (1,4-BD), and gamma-butyrolactone (GBL) in various animal tissues (kidney, muscle, heart, liver, blood, brain cortex, thalamus, hypothalamus, hippocampus, or pons), an original gas chromatographic/mass spectrometric method with a automated solid-phase extraction by Oasis MCX cartridges on a Gilson Aspec Xli was developed. Using such apparatus allowed the limit of detection (LOD) of target compounds to be significantly lowered (LOD: 0.027, 0.025, and 5.7 microg/mL for GHB, 1,4-BD, and GABA, respectively, in 200 microL or microg of sample). After validation of each analytical step, the satisfactory performances of the apparatus in conjunction with the rapidity and ease of the extraction step make it suitable for simultaneous assay of GHB, 1,4-BD, GBL, and GABA. The method was used to test the correlation between GHB levels in tissues obtained at different times after death of male Sprague-Dawley rats and the postmortem interval. Preliminary results show a linear increase of GHB levels in relation to time of death in thoracic blood and central nervous system of animals kept at 15 and 20 degrees C.

Topics: 4-Butyrolactone; Animal Structures; Animals; Butylene Glycols; Calibration; Central Nervous System; gamma-Aminobutyric Acid; Gas Chromatography-Mass Spectrometry; Male; Postmortem Changes; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Sodium Oxybate; Solid Phase Extraction; Temperature; Time Factors

Gamma-hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study tried to increase the selectivity of the discriminative stimulus effects of GHB by training animals to discriminate GHB from compounds that share pharmacological mechanisms with GHB. In comparison with a previous GHB versus saline discrimination (group 1), rats were trained to discriminate GHB (200 mg/kg) either from saline and the GABA(B) agonist baclofen (3.2 mg/kg) (group 2) or from saline, baclofen, and the positive GABA(A) modulator diazepam (1 mg/kg) (group 3). In all groups, GHB produced more than 80% GHB-appropriate responding. Baclofen produced 84% GHB-appropriate responding in group 1 but less than 30% in groups 2 and 3. Diazepam produced 68% GHB-appropriate responding in group 1, 30% in group 2, and only 5% in group 3. The GABA(B) receptor antagonists CGP35348 [3-[aminopropyl(diethoxymethyl)phosphinic acid] and CGP52432 [3-[[[((3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid] attenuated the discriminative stimulus effects of GHB; CGP35348 did so with similar potency in all groups, but CGP52432 was significantly less potent in groups 2 and 3 than in group 1. In all groups, the GHB antagonist NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid] partially attenuated the discriminative stimulus effects of GHB. The selective GHB receptor ligand UMB86 (4-hydroxy-4-napthylbutanoic acid sodium) tended to attenuate the discriminative stimulus effects of GHB more in group 3 than in the other groups. The finding that animals can discriminate GHB from baclofen is further evidence that the effects of GHB and baclofen are not identical. Effects that GHB does not share with baclofen may involve GHB receptors or differential interactions with GABA(B) receptors.

Topics: 4-Butyrolactone; Anesthetics, Intravenous; Animals; Baclofen; Benzocycloheptenes; Benzylamines; Butylene Glycols; Diazepam; Discrimination, Psychological; Dithiothreitol; Dose-Response Relationship, Drug; GABA Agonists; GABA Antagonists; GABA Modulators; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Male; Organophosphorus Compounds; Phosphinic Acids; Rats; Rats, Sprague-Dawley; 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

The effects of 1,4-butanediol, gamma-hydroxybutyrate (GHB), and (+/-)-baclofen on food-maintained responding in rats were assessed before, during, and after chronic treatment with 1,4-butanediol. Six weeks of treatment with 1,4-butanediol (twice daily, 320 mg/kg for 3 weeks followed by 560 mg/kg for 3 weeks) decreased sensitivity to the rate-decreasing effects of (+/-)-baclofen and GHB without changing sensitivity to 1,4-butanediol. Sensitivity to (+/-)-baclofen and GHB returned to control values 2-3 weeks after discontinuation of treatment. These data suggest that tolerance to the effects of GHB or its precursors might result from changes in GABA(B) mechanisms.

Topics: Animals; Baclofen; Butylene Glycols; Dose-Response Relationship, Drug; Drug Tolerance; Male; Rats; Rats, Sprague-Dawley; Reaction Time; Sodium Oxybate

Possible effects of reinforcer type on the results of drug discrimination studies have not been examined systematically, but different deprivation operations and differentially effective reinforcers might well influence outcomes.. Therefore, this study examined the influence of reinforcer (food or water) as well as route of administration (IP or IG) on gamma-hydroxybutyrate (GHB) discrimination.. Four separate groups of six rats were trained under a resetting fixed-ratio schedule to discriminate between 300 mg/kg GHB and vehicle under these conditions, then generalization tests were conducted with gamma-butyrolactone (GBL), 1,4-butanediol (1,4-BD), ethanol, and ethanol plus 150 mg/kg GHB.. Food maintained significantly higher response rates than water, but there were no significant differences among the four training groups in response accuracy or sessions required to meet the discrimination criterion. Training conditions significantly affected the results of stimulus generalization tests. The IG-Water group was most sensitive to a lower dose of GHB, and only the IP-Water group failed to generalize to orally-administered GHB. Gamma-butyrolactone and 1,4-butanediol fully substituted in all except the IP-Food group. Ethanol did not fully substitute for GHB in any group, and the combination of GHB (150 mg/kg) and ethanol did not have additive effects.. These results demonstrate that methodological variables during drug discrimination training can certainly influence the results of stimulus generalization. Future investigations into the behavioral and/or physiological mechanisms that account for these effects are warranted.

Topics: 4-Butyrolactone; Animals; Butylene Glycols; Central Nervous System Depressants; Conditioning, Operant; Discrimination Learning; Ethanol; Food; Injections, Intraperitoneal; Intubation, Gastrointestinal; Male; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Sodium Oxybate; Solvents; Water

gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. This study characterized the role of GABA(A), GABA(B), and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/-)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor gamma-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA(A) receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348 antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA(B) mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies.

Topics: 4-Butyrolactone; Animals; Butylene Glycols; Conditioning, Operant; Discrimination, Psychological; Dose-Response Relationship, Drug; Food; GABA Agonists; GABA Modulators; GABA-B Receptor Antagonists; Kinetics; Male; Muscimol; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology; Sodium Oxybate

A solvent, 1,4-butanediol, is also abused as a recreational drug. In mammals, 1,4-butanediol is metabolized into gamma-hydroxybutyric acid (GHB), which stimulates metabotropic gamma-aminobutyric acid (GABA) GABAB and putative GHB receptors. Here we show that in vivo injection of 1,4-butanediol into adult Drosophila leads to GHB synthesis (GHB was detectable 5 min after 1,4-butanediol injection and increased dramatically 1-2 h later). This synthesis of GHB was accompanied by an impairment of locomotor activity that was mimicked by a direct injection of GHB into flies. We propose Drosophila as a model to study the molecular actions of 1,4-butanediol and GHB.

Topics: Animals; Butylene Glycols; Drosophila melanogaster; Gas Chromatography-Mass Spectrometry; Male; Sodium Oxybate; Time Factors

Topics: Adult; Blood Pressure; Butylene Glycols; Charcoal; Consciousness Disorders; Delirium; Diagnosis, Differential; Electrocardiography; Gastric Lavage; Humans; Male; Poisoning; Sodium Oxybate; Sweating

This article describes two methods for the determination of 1,4-butanediol and gamma-hydroxybutyrate in human plasma and urine using capillary gas chromatography. For 1,4-butanediol, plasma or urine samples (500 microl) were extracted by protein precipitation whereas for gamma-hydroxybutyrate, plasma or urine samples (500 microl) were extracted and derivatised with BF3-butanol. The compounds were separated on a Supelcowax-10 column and detection was achieved using a flame ionization detector. The methods are linear over the specific ranges investigated, accurate (with a percentage of the nominal concentration <109.8%) and showed intra-day and inter-day precision within the ranges of 5.0-12.0 and 7.0-10.1%, respectively. No interferences were observed in plasma and urine from hospitalized patients.

Topics: Butylene Glycols; Chromatography, Gas; Humans; Reproducibility of Results; Sensitivity and Specificity; Sodium Oxybate

1,4-Butanediol (1,4-BD) is the dihydroxy precursor of gamma-hydroxybutyrate (GHB), a popular recreational drug that has been banned by the United States Food and Drug Administration (FDA) and controlled as a federal schedule I drug. 1,4-BD is enzymatically converted in vivo to GHB by alcohol dehydrogenase (ADH), and overdoses can result in coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death. Presently, there is no antidote. We pretreated CD-1 mice with the ADH antagonist, 4-methylpyrazole (4-MP), to determine if blocking ADH can prevent or decrease toxicity from 1,4-BD overdose. Pretreatment with 4-MP increased the Toxic Dose-50 (TD(50)) of 1,4-BD for the righting reflex from 585 mg/kg (95% CI, 484-707 mg/kg) in control mice to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in pretreated mice. Pretreatment with 4-MP also increased the TD(50) of 1,4-BD for the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly decreased the toxicity of 1,4-BD in CD-1 mice, presumably by inhibiting its ADH biotransformation to GHB. 4-MP warrants further investigation as a potential antidote for this increasingly abused drug.

Topics: Alcohol Dehydrogenase; Animals; Antidotes; Biotransformation; Butylene Glycols; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fomepizole; Male; Mice; Postural Balance; Pyrazoles; Sodium Oxybate

1,4-Butanediol is an industrial solvent that, when ingested, is converted to gamma-hydroxybutyrate, a drug of abuse with depressant effects, primarily on the central nervous system. After reports of toxic effects of gamma-hydroxybutyrate and its resultant regulation by the federal government, 1,4-butanediol and gamma-butyrolactone, another precursor of gamma-hydroxybutyrate and an industrial solvent, began to be marketed as dietary supplements. We investigated reports of toxic effects due to the ingestion of 1,4-butanediol and reviewed the related health risks.. From June 1999 through December 1999, we identified cases of toxic effects of 1,4-butanediol involving patients who presented to our emergency departments with a clinical syndrome suggesting toxic effects of gamma-hydroxybutyrate and a history of ingesting 1,4-butanediol and patients discovered through public health officials and family members. We used gas chromatography-mass spectrometry to measure 1,4-butanediol or its metabolite, gamma-hydroxybutyrate, in urine, serum, or blood.. We identified nine episodes of toxic effects in eight patients who had ingested 1,4-butanediol recreationally, to enhance bodybuilding, or to treat depression or insomnia. One patient presented twice with toxic effects and had withdrawal symptoms after her second presentation. Clinical findings and adverse events included vomiting, urinary and fecal incontinence, agitation, combativeness, a labile level of consciousness, respiratory depression, and death. No additional intoxicants were identified in six patients, including the two who died. The doses of 1,4-butanediol ingested ranged from 5.4 to 20 g in the patients who died and ranged from 1 to 14 g in the nonfatal cases.. The health risks of 1,4-butanediol are similar to those of its counterparts, gamma-hydroxybutyrate and gamma-butyrolactone. These include acute toxic effects, which may be fatal, and addiction and withdrawal.

Topics: Adult; Butylene Glycols; Dietary Supplements; Fatal Outcome; Female; Humans; Male; Psychomotor Agitation; Pulmonary Edema; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders; Unconsciousness; Vomiting

Topics: Adult; Butylene Glycols; Emergencies; Female; Humans; Male; Sodium Oxybate; Substance Withdrawal Syndrome

The formation of 4-[1,4-13C]hydroxybutyric acid ([13C]gamma-hydroxybutyric acid; [13C]GHB) in rat brain was studied following intracerebroventricular (i.c.v.) administration of either 4-[1,4-13C]aminobutyric acid ([13C]GABA or 1,4-[1,4-13C]butanediol ([13C]1,4-BD) to awake, freely moving animals. GHB and [13C]GHB were measured with a gas chromatographic mass spectrometric (GC/MS) technique designed to detect the lactone derivative of GHB with the acid or lactone being determined by conditions of tissue extraction. [13C]GHB was detected following i.c.v. administration of [13C]GABA with a turnover rate of 2.04 nmol/g tissue/hr and [13C]1,4-BD with a turnover rate of 1.4 nmol/g/hr. The formation of [13C]GHB from [13C]GABA was blocked by an inhibitor of GABA-transaminase, but this drug had no effect on the formation of [13C]GHB from [13C]1,4-BD. The latter pathway was also unaffected by alcohol dehydrogenase inhibitors, compounds which block this pathway in the periphery. Further, in the course of these experiments, naturally occurring endogenous gamma-butyrolactone (GBL) was detected in rat brain in a concentration of 200 pmol/g tissue weight, but lactonization in vivo of [13C]GHB formed from either labeled GABA or 1,4-BD was not demonstrated. These data confirm two separate pathways of synthesis for GHB in brain, demonstrate the presence of GBL in brain, and illustrate the utility of a new GC/MS technique for analysis of GHB and for GBL which does not involve extensive derivatization.

Topics: Animals; Brain; Butylene Glycols; gamma-Aminobutyric Acid; Hydroxybutyrates; Kinetics; Lactones; Male; Rats; Rats, Inbred Strains; Sodium Oxybate

Topics: Animals; Brain Chemistry; Butylene Glycols; Gas Chromatography-Mass Spectrometry; Hydroxybutyrates; Liver; Male; Rats; Rats, Inbred Strains; Sodium Oxybate

We have investigated the interaction of 1,4 butanediol (1,4 BD) with ethanol and the involvement of the major metabolite of 1,4 BD, gamma-hydroxybutyric acid (GHB) in the ability of 1,4 BD to produce behavioral and EEG changes in rat as well as the toxic side effects of 1,4 BD. Behavioral, electrical, and biochemical studies in rats suggest that the effects of 1,4 BD are indeed mediated by GHB. Further, ethanol appears to block conversion of 1,4 BD to GHB. 1,4 BD however potentiates some of the behavioral effects of ethanol perhaps by a mechanism of action similar to that of other alcohols. Thus 1,4 BD appears to have two types of pharmacologic actions, one attributable to its conversion to GHB and the other an inherent property of the diol itself.

Topics: Animals; Behavior, Animal; Biotransformation; Brain; Butylene Glycols; Drug Interactions; Electroencephalography; Ethanol; Hydroxybutyrates; Liver; Male; Rats; Rats, Inbred Strains; Sodium Oxybate