Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan of Caenorhabditis elegans via DAF-16 and HSF-1.

Secoisolariciresinol diglucoside (SDG) is a phytoestrogen and rich in food flaxseed, sunflower seeds, and sesame seeds. Among the beneficial pharmacological activities of SDG on health, many are age related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. Thus, we investigated if SDG had an effect on antiaging in Caenorhabditis elegans (C. elegans). Our results showed that SDG could extend the lifespan of C. elegans by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine (6-OHDA), and decrease the toxicity of Aß protein in C. elegans. SDG could increase the expression of the downstream genes of DAF-16, DAF-12, NHR-80, and HSF-1 at mRNA level. SDG could not extend the lifespan of mutants from genes daf-16, hsf-1, nhr-80, daf-12, glp-1, eat-2, and aak-2. The above results suggested that SDG might enhance the stress resistance, delay the progression of aging-related diseases, and extend the lifespan of C. elegans via DAF-16 and HSF-1.

[Acute severe oral poisoning with 1,4-butandiol and ethanol with the development of coma]. / Ostroe tyazheloe peroral'noe otravlenie 1,4-butandiolom i etanolom s razvitiem komatoznogo sostoyaniya.

A case of acute oral poisoning by 1.4-butanediol, complicated by the development of severe hypoxia in a 34-year-old patient actively engaged in bodybuilding, is presented. The psychoactive substance was used by the patient to increase sexual activity and physical stamina. The duration of systematic daily intake was 4 months. The toxicogenic stage of acute poisoning was caused by a single dose of 50 ml of undiluted 13% 1.4-butanediol together with ethanol, manifested by convulsive syndrome, depression of consciousness to the level of coma II, acute respiratory failure with aspiration syndrome, respiratory acidosis (pH 7.22; partial pressure carbon dioxide 61.2 mm Hg), lactic acidosis up to 7 mmol / L, hyperammonemia up to 240 µmol / L, cerebral edema (decrease in white matter density to 21.6 ± 1.7 HU units), loss of vascular tone resistance (pareso arterioles) and a significant increase in cerebral blood flow rate to 115 ± 20.1 ml / 100 g per minute, increasing the volume of extracellular fluid (+ 130% of the proper volumes). Intensive therapy was complex, including infusion and detoxification therapy, correction of acid-base disorders, hypoxic disorders by using a substrate antihypoxant (Cytoflavin) in a daily dosage of 0.57 ml / kg body weight daily, for 9 days. The article discusses the toxicokinetics and toxicodynamics of 1.4-butanediol, radiation diagnostics and the clinical picture of acute poisoning, the features of its course, and pathogenetic approaches to therapy.

1,4-Butanediol overdose mimicking toxic alcohol exposure.

Context: 1,4-butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) analogue with a similarly narrow therapeutic window that is becoming a more common cause of recreational overdose. Reports of confirmed exposures are limited.Case details: A 44 year-old man who had consumed alcohol subsequently became unconscious after ingesting what was thought to be GHB. The presentation was not entirely consistent with GHB poisoning, including a longer duration of unconsciousness and features that mimicked toxic alcohol exposure including a high anion gap metabolic acidosis (HAGMA) and osmol gap. The patient was treated supportively with intubation, haemodiafiltration and intravenous ethanol until the diagnosis was refined using specific laboratory testing. The concentration of 1,4-BD was the highest reported in the literature and the outcome favourable.Discussion: This case highlights pharmacokinetic issues peculiar to 1,4-BD, including the interaction with ethanol which delays the onset of psychoactive effects from 1,4-BD's metabolite GHB, and dose-dependent pharmacokinetics. In overdose, 1,4-BD can induce a HAGMA and other features of toxic alcohol poisoning. Managing an unconscious patient with these features can prompt certain treatments until the diagnosis is refined, which can require specific laboratory testing to identify the culprit. The actual risk of toxic alcohol and other causes is adjusted on a case-by-case basis from the history of exposure and local epidemiology of substance use and poisoning.

Quantification of GHB and GHB-GLUC in an 1,4-butanediol intoxication: A case report.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound with known action at the neural level. Its psychoactive effects led to an illicit use context including recreational purposes, muscle building effects in bodybuilders and drug-facilitated crimes, specifically in sexual assaults. Besides the misuse of the main compound, there are precursors like Gammabutyrolactone (GBL) and 1,4-butanediol (1,4-BD), usually non controlled substances, becoming a much easier way to obtain the target-compound. The authors present the first reported intoxication case in Portugal with 1,4-Butanediol, including the quantification of GHB and GHB-GLUC in serum, by GC-MS/MS TQD. A suspicious liquid and a serum sample were sent by an hospital ER and analysed by GC-MS-single quadrupole and GC-MS/MS TQD, respectively. A methodology including protein precipitation and GC-MS/MS TQD analysis was used to detect and quantify GHB and GHB-GLUC in serum. Toxicological analysis revealed the presence of 1,4-Butanediol in the liquid and GHB [171 mg/L] and GHB-GLUC [13,7 mg/L] in serum. The victim reverted the coma with no neurological sequelae. This was the first detected case, in Portugal, with 1,4-Butanediol, suggesting that it is important to be aware that consumers have different options to obtain illicit compounds, such as GHB. On the other hand, GHB-GLUC was identified and quantified for the first time in a real case, due to intoxication. This case highlights the importance of analysing all samples for active compounds, precursors and metabolites that can lead to the main intoxication origin.

Fatal Overdose of Gamma-hydroxybutyrate Acid After Ingestion of 1,4-Butanediol.

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.

The clinical toxicology of γ-hydroxybutyrate, γ-butyrolactone and 1,4-butanediol.

INTRODUCTION: 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. METHODS: 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. EPIDEMIOLOGY: 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. MECHANISMS OF ACTION: 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. TOXICOKINETICS: 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. CONCLUSIONS: 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.

Coma in a 20-month-old child from an ingestion of a toy containing 1,4-butanediol, a precursor of gamma-hydroxybutyrate.

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.

Medical and legal confusion surrounding gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD).

BACKGROUND: 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. AIM: 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. DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Resuscitative treatments on 1,4-butanediol mortality in mice.

STUDY OBJECTIVE: Recent reports on fatalities associated with overdoses from 1,4-butanediol (1,4-BD), a precursor of the drug of abuse gamma-hydroxybutyric acid (GHB), pose the need for investigations focusing on possible pharmacologic remedies. Accordingly, the present study investigates whether 4-methylpyrazole (4-MP; also termed fomepizole and Antizol), an inhibitor of alcohol dehydrogenase (the enzyme involved in the first step of the conversion of 1,4-BD into GHB), and the gamma-aminobutyric acid B (GABAB) receptor antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), provides protection against 1,4-BD-induced mortality in CD1 mice. METHODS: Two sets of experiments were conducted with mortality as the outcome measure. In all experiments, mice were initially treated with a lethal dose of 1,4-BD (3 g/kg, intragastric [i.g.]). In the first set of experiments (dose-response curves), once mice had displayed clear signs of 1,4-BD intoxication, animals were randomly allocated in separate groups (n=10) and treated acutely with either 4-MP (vehicle, 3, 10, 30, and 100 mg/kg, intraperitoneal [i.p.]) or SCH 50911 (vehicle, 75, 150, and 300 mg/kg, i.p.). Mortality was recorded every hour for the first 9 hours and 12, 18, and 24 hours after 1,4-BD injection. In the second set of experiments (time course), mice were randomly allocated in separate groups (n=10). A single dose of either 4-MP (30 mg/kg, i.p.) or SCH 50911 (150 mg/kg, i.p.) was administered 15, 30, 60, 90, or 120 minutes after administration of 3 g/kg 1,4-BD (i.g.). Again, mortality was recorded every hour for the first 9 hours and 12, 18, and 24 hours after 1,4-BD injection. RESULTS: In the dose-response experiments, the acute administration of 4-MP and SCH 50911 exerted a dose-dependent resuscitative effect in mice acutely intoxicated by 3 g/kg 1,4-BD. Specifically, 30 and 100 mg/kg 4-MP and 150 mg/kg SCH 50911 protected all treated mice against 1,4-BD-induced mortality. Conversely, all mice treated with 4-MP- and SCH 50911-vehicle died. In the time-course experiments, protection induced by 30 mg/kg 4-MP was complete when administered up to 90 minutes after 1,4-BD injection. Vice versa, the complete protection induced by 150 mg/kg SCH 50911 progressively diminished as the time between 1,4-BD and SCH 50911 administration was increased from 15 to 120 minutes. CONCLUSION: These results indicate that both 4-MP and SCH 50911 protected against mortality induced by 1,4-BD. Further, these results suggest that 1,4-BD-induced mortality in mice is a result of conversion of 1,4-BD into GHB and GHB-induced activation of the GABAB receptor. Because both 4-MP and GABAB receptor antagonists are available for human use, clinical studies on their ability to reverse the consequences of 1,4-BD and GHB intoxication, including fatal events, might be considered.

[GHB, GBL and butanediol poisonings--a serious problem in Western Sweden]. / GHB-, GBL- och butandiolförgiftningar--ett allvarligt problem i Västsverige.

Acute poisoning with GHB (Gamma-hydroxybutyrate, Gamma-hydroxybutyric acid) has been an increasing medical and social problem during the last decade in Sweden, especially on the west coast. The number of poisonings decreased in the beginning of this millennium but has again increased during the last years. At the same time the number of seizures by the police has increased similarly as well as the number of drug-related deaths. During 2004 the number of GHB-abuse related deaths in western Sweden was seven, approximately the same figures as for heroin. Two other substances which are transformed to GHB in the human body, GBL (gamma-butyrolactone) and 1,4-butanediol, have during the last years presented themselves among the same users as for GHB. Since GBL and butanediol are not classified as illicit drugs the possibilities for the police force to intervene and capture the drugs are severely restricted. Intoxication by GBL and butanediol has shown to be as dangerous as intoxication by GHB. Acute intoxications and abuse of these drugs is still a serious medical and social problem. A legal classification of GBL and butanediol as narcotics appears to be medically motivated.

Survival of massive gamma-hydroxybutyrate/1,4-butanediol overdose.

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.

Intoxication due to 1,4-butanediol.

We report a case of intoxication resulting from the ingestion of a liquid, sold in the illicit market as "liquid ecstasy," which was found to contain 1,4-butanediol, a metabolic precursor of gamma-hydroxybutiric acid (GHB). Identification of the substance in the liquid was performed by gas chromatography-mass spectrometry (GC-MS). The toxicological analysis of blood, urine and gastric content of the victim was performed by immunoassay and gas chromatography with nitrogen-phosphorus detection as screening techniques and by means of GC-MS for confirmation and quantitation of 1,4-butanediol and GHB. The following drug concentrations were found: 82 microg/ml (blood), 401 microg/ml (urine) and 7.4 microg/ml (gastric content) for 1,4-butanediol and 103 microg/ml (blood), 430.0 microg/ml (urine) for GHB. In addition to these, other drugs detected and their blood concentration found in this case were methylenedioxymethylamphetamine (MDMA) 0.23 microg/ml and its metabolite methylenedioxyphenylamphetamine (MDA) 0.10 microg/ml. In the urine, a concentration of 0.10 microg/ml of benzoylecgonine was also found.

Treatment of a 1,4-butanediol poisoning with fomepizole.

BACKGROUND: Toxicity of 1,4-butanediol, an industrial solvent and a substance of abuse, is still misunderstood and not well documented. To date, only supportive treatments are used in this poisoning. CASE REPORT: The case of a 43-year-old man who ingested 30 mL of a homemade 1,4-butanediol solution and who developed general seizures and coma has been reported here. An intravenous loading dose of fomepizole 10 mg/kg was started on admission and followed by two other doses of 10 mg/kg every 12 hour. He awoke shortly after fomepizole administration. Initial plasma 1,4-butanediol and gamma-hydroxybutyric acid concentrations, measured by gas chromatography-mass spectrometry, were 24 and 222 mg/L, respectively. Subsequent 1,4-butanediol and gamma-hydroxybutyric acid determination suggest that there was some further formate of gamma-hydroxbutyric acid after fomepizole was administered. CONCLUSION: Fomepizole administration appeared safe in this 1,4-butanediol-intoxicated patient. It is unknown whether fomepizole influenced his clinical course, but the rapid awakening observed suggests that it may have been usefuL Further experience is needed, however, to define the efficacy of this antidotal therapy in 1,4-butanediol intoxication.

Application of a convenient extraction procedure to analyze gamma-hydroxybutyric acid in fatalities involving gamma-hydroxybutyric acid, gamma-butyrolactone, and 1,4-butanediol.

The most common chemicals that can be ingested and lead to greater than endogenous levels of gamma-hydroxybutyric acid (GHB) in decedents are salts of GHB, gamma-butyrolactone (GBL), and 1,4-butanediol (BD). Results for three deaths involving the ingestion of one or another of these three chemicals, which led to findings of GHB in the decedents, are presented. An extraction procedure that facilitates the quantitation of GHB was developed. If present in the same specimen, both GHB and GBL can be quantitated. To determine the GBL concentration, the specimen is first analyzed for existing GHB, the GBL is then converted to GHB, and the analysis is repeated. The difference between the results in molarity units can yield the GBL concentration. A separate procedure was utilized for estimating concentrations of BD. Specimens analyzed included urine, blood, ocular fluid, brain, and solutions consumed by the decedents prior to death. The procedures were found to be convenient in as much as they are relatively rapid, precise, and economical.

[GHB--dangerous, addictive and uncontrollable "party drug"]. / GHB--farlig, beroendeframkallande och svårkontrollerad "partydrog".

This report reviews the pharmacology, toxicity and abuse pattern of gamma-hydroxybutyrate (GHB). The legislative changes pertaining to this substance are also addressed. Examples of abuse, driving under the influence and fatal intoxication are given. It is concluded that GHB is widely abused, particularly among the younger generation, and that further cases of severe intoxication are likely to occur as long as the substance is easily available from countless sources, including via the Internet. Despite the classification of GHB as a narcotic in Sweden and several other countries, continued problems are expected since the precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD) are widely--and legally--available.