Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review

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.     

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.     

Effects of gamma-hydroxybutyrate (GHB) on schedule-controlled responding in rats: role of GHB and GABAB receptors

Gamma-hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is an increasingly popular drug of abuse and was recently approved for the treatment of narcolepsy (Xyrem). GHB and GABA receptors have been implicated in mediating effects of GHB; however, the relative importance of each of these receptors is unclear. This study evaluated the effects of selective antagonists in combination with GHB and related compounds on schedule-controlled responding. Eight male Sprague-Dawley rats responded under a fixed-ratio schedule of food presentation. Cumulative dose-effect curves were generated and ED50 values calculated to evaluate the relative potency at decreasing responding. The rank-order potency was as follows: diazepam = baclofen > gamma-butyrolactone (GBL) > 1,4-butanediol (1,4-BDL) = GHB. All compounds decreased responding 20 min after administration. The duration of action of diazepam, GHB, and GBL was shorter than that of 1,4-BDL and baclofen. p-3-Aminopropyl-p-diethoxymethyl phosphinic acid (CGP 35348) antagonized the rate-decreasing effects of baclofen and not GHB; flumazenil antagonized the effects of diazepam and not GHB. The GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) did not attenuate the rate-decreasing effects of GHB, baclofen, or diazepam; larger doses of NCS-382 further decreased rate of responding when given in combination with each of these compounds. These studies show that GBL, 1,4-BDL, and GHB differ significantly in potency and duration of action. The ability of CGP 35348 to antagonize the rate-decreasing effects of baclofen may be limited by the involvement of multiple GABAB receptor subtypes and the lack of antagonism of GHB by NCS-382 may be due to its own GHB-like effects.     

New drugs of abuse

Newer drugs of abuse, such as MDMA, GHB, GBL, 1,4-BD and ketamine, are frequently used in the settings of raves and are often promoted on the internet. The popularity of these agents is increasing; therefore, emergency physicians should become familiar with the clinical presentations and management of the toxicity induced by these agents.     

Gammabutyrolactone: withdrawal syndrome resembling delirium tremens

Gammabutyrolactone (GBL, Liquid Ecstasy) is an emerging drug of abuse in the United Kingdom. It is metabolised to gamma hydroxybutyrate (GHB) in the body and has cross-tolerance with alcohol. We report a case of acute withdrawal resembling delirium tremens: a young male recognised to be withdrawing from GBL was treated with high doses of benzodiazepines. At lower doses GBL and GHB cause euphoria, disinhibition and increased libido. At higher doses they cause CNS and respiratory depression. The risk of toxicity is increased markedly by co-ingestion of other depressant substances such as alcohol, benzodiazepines or opiates. UK Home Office reclassified GHB as Class C controlled substance; however, GBL remains unclassified and it is easily available. Symptoms of withdrawal appear rapidly and the delirium evolves more rapidly. Early symptoms include anxiety, insomnia, mild tremor and intermittent tachycardia. Users of GBL should be aware of the risk of dependence in addition to toxicity. The police and criminal justice system should also be aware of its potential for misuse as a date rape drug. Professionals should be able to recognise and treat the withdrawal syndrome. Greater restrictions should be placed on its availability, and the Home Office should urgently consider reclassifying GBL as a controlled substance.     

GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier

gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V(max) = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.     

Isopropanol poisoning

Introduction. Isopropanol is a clear, colorless liquid with a fruity odor and a mild bitter taste. Most commonly found domestically as rubbing alcohol, isopropanol is also found in numerous household and commercial products including cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals. Aim. The aim of this review is to critically review the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning. Methods. OVID MEDLINE and ISI Web of Science were searched to November 2013 using the words “isopropanol”, “isopropyl alcohol”, “2-propanol”, “propan-2-ol”, and “rubbing alcohol” combined with the keywords “poisoning”, “poison”, “toxicity”, “ingestion”, “adverse effects”, “overdose”, or “intoxication”. These searches identified 232 citations, which were then screened via their abstract to identify relevant articles referring specifically to the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning; 102 were relevant. Further information was obtained from book chapters, relevant news reports, and internet resources. These additional searches produced eight non-duplicate relevant citations. Epidemiology. The majority of isopropanol exposures are unintentional and occur in children less than 6 years of age. Although isopropanol poisoning appears to be a reasonably common occurrence, deaths are rare. Toxicokinetics. Isopropanol is rapidly absorbed following ingestion with peak plasma concentrations occurring within 30 min. It can also be absorbed following inhalation or dermal exposure. Isopropanol is widely distributed with a volume of distribution of 0.45–0.55 L/kg. Isopropanol is metabolized by alcohol dehydrogenase to acetone, acetol and methylglyoxal, propylene glycol, acetate, and formate with conversion of these metabolites to glucose and other products of intermediary metabolism. The elimination of isopropanol is predominantly renal, though some pulmonary excretion of isopropanol and acetone occurs. In one case 20% of the absorbed dose was eliminated unchanged in urine, with the remainder excreted as acetone and metabolites of acetone. The elimination half-life of isopropanol is between 2.5 and 8.0 h, whereas elimination of acetone is slower with a half-life following isopropanol ingestion of between 7.7 and 27 h. Mechanisms of toxicity. While the exact mechanism of action of isopropanol has not been fully elucidated, brain stem depression is thought to be the predominant mechanism. While the clinical effects are thought to be mostly due to isopropanol, acetone may also contribute. Clinical features. The major features of severe poisoning are due to CNS and respiratory depression, shock, and circulatory collapse. The most common metabolic effects are an increased osmol (osmolal) gap, ketonemia, and ketonuria. Diagnosis. Poisoning can be diagnosed using the measurement of isopropanol serum concentrations, though these may not be readily available. Diagnosis is therefore more typically made on the basis of the patient's history and clinical presentation. An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis, along with a fruity or sweet odor on the breath and CNS depression support the diagnosis. Management. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Hemodialysis enhances elimination of isopropanol and acetone and should be considered in very severe poisoning. Conclusions. Severe isopropanol poisoning results in CNS and respiratory depression and circulatory collapse. Treatment primarily consists of symptom-directed supportive care. Although hemodialysis increases the elimination of isopropanol and acetone substantially, it should only be considered in severe life-threatening poisonings. Patients usually make a full recovery provided they receive prompt supportive care.     

Gamma Hydroxybutyric Acid (GHB) Intoxication

Gamma hydroxybutyric acid (GHB) is a naturally occurring analog of gamma-aminobutyric acid (GABA) that has been used in research and clinical medicine for many years. In the past decade it has become very popular as a dietary supplement and recreational drug. Acute overdose leads to profound alteration of mental status and variable amounts of respiratory depression. With proper management, most patients recover fully within six hours. However, respiratory arrest and death have been reported in severe GHB intoxication. In addition to acute overdose, there is a GHB withdrawal syndrome that is similar to sedative/hypnotic and ethanol withdrawal. Recently several congeners of GHB, gamma butyrolactone and 1,4-butanediol, have emerged as drugs of abuse and show toxidromes similar to GHB. Emergency physicians should be familiar with the presentation and management of GHB-related emergencies.     

The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies

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.     

Electrophysiological correlates of respiratory failure in acute organophosphate poisoning: Evidence for differential roles of muscarinic and nicotinic stimulation

Background. Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at these different phases may have important clinical implications. Objective. To compare the electrophysiological findings in patients with early and late respiratory failure following acute OP poisoning. Methods. A prospective observational case series of consenting symptomatic patients with acute OP poisoning were assessed with daily physical examinations and repetitive nerve stimulation (RNS) studies. RNS was done on right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. Outcomes such as need for ventilation and development of intermediate syndrome (IMS) were noted. Early respiratory failure was defined as occurring within 24 hours of ingestion. Results. Seventy-eight patients were recruited for the clinical and electrophysiological study and of those 59 (75.6%) patients had ingested chlorpyrifos. Seven patients developed respiratory failure within 24 hours of ingestion with overt muscarinic signs. They had no electrophysiological abnormalities at median and ulnar nerves before intubation. Three of them later developed “forme fruste” IMS. Five other patients developed late respiratory failure after 24 hours of ingestion, and all of them showed progressive RNS changes indicating severe IMS prior to intubation. Conclusion. The normal RNS in all patients developing early respiratory failure suggests that it is due to a central nervous system (CNS) and muscarinic effect. This emphasizes the need for early rapid atropinisation as a priority, combating the nicotinic effects being less urgent. This is in contrast with the late respiratory failure, which has been shown to be associated with neuromuscular dysfunction. Further studies are needed to quantify CNS and muscarinic dysfunction to assist in the development of better treatments for the severe and early OP poisoning.     

The Discriminative stimulus effects of gamma-hydroxybutyrate and related compounds in rats discriminating baclofen or diazepam: The role of GABA(B) and GABA(A) receptors

The discriminative stimulus effects of gamma-hydroxybutyrate (GHB) can be mimicked by GABA(A) receptor-positive modulators (e.g., diazepam) and GABA(B) receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors gamma-butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABA(A) receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABA(B) receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABA(B), mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABA(A) mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.     

A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol

We describe a case of withdrawal from the gamma hydroxybutyric acid (GHB) precursors gamma butyrolactone and 1,4-butanediol. Symptoms included visual hallucinations, tachycardia, tremor, nystagmus, and diaphoresis. Administration of benzodiazepines and phenobarbital successfully treated the withdrawal symptoms. As predicted from the metabolism of gamma butyrolactone and 1,4-butanediol to GHB, the symptoms were nearly identical to those reported from GHB withdrawal. Because GHB is now illegal in the United States, individuals have begun abusing the legal and easier to acquire GHB precursors. More frequent cases of both abuse and withdrawal from these GHB precursors can be expected.     

Trans crystallization behavior and strong reinforcement effect of cellulose nanocrystals on reinforced poly(butylene succinate) nanocomposites

Biodegradable poly(butylene succinate) (PBS) nanocomposites are polymerized via in situ polymerization of succinic acid (SA) with cellulose nanocrystal (CNC)-loaded 1,4-butanediol (1,4-BD) mixtures. As reinforcement fillers, whisker-like CNCs are first dispersed in alcohol and sequentially spray-dried, before adding them to 1,4-BD. During the polymerization, the remains of sodium sulfonate in the CNC surfaces retard the polycondensation reaction, which is carefully controlled for the CNC-loaded systems. For the 0.1–1.0 wt% CNC-loaded PBS nanocomposites, it is found the nano-fillers are sufficiently dispersed to induce different crystallization behavior of the matrix polymer. The CNCs may initially act as heterogeneous nucleation sites of the molten PBS chains, during melt crystallization. In this case, most of them tend to be pushed out from the growing crystallites, which develop different nanocomposite morphologies with increasing CNC content. Among the resulting nanocomposites, the 0.1 wt% CNC-loaded system shows the highest tensile strength of 65.9 MPa, similar to that of nylon 6, as a representative engineering polymer as well as 2 fold elongation at break compared with Homo PBS. The in situ polymerized CNC-loaded PBS nanocomposites are expected to be a 100% biomass material for a virtuous cycle of biorefinery. Moreover, they demonstrate that the CNC-loaded PBS nanocomposite with a low CNC loading content can be used in various commercial applications for pollution abatement.

Biodegradable poly(butylene succinate) (PBS) nanocomposites are polymerized via in situ polymerization of succinic acid (SA) with cellulose nanocrystal (CNC)-loaded 1,4-butanediol (1,4-BD) mixtures.     

Discriminative stimulus effects of gamma-hydroxybutyrate in pigeons: role of diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors

gamma-Hydroxybutyrate (GHB) is an emerging drug of abuse with multiple mechanisms of action. This study is part of an effort to examine the role of GHB, GABA(A), and GABA(B) receptors in the discriminative stimulus (DS) effects of GHB. In pigeons trained to discriminate 100 mg/kg GHB from saline, GHB and its precursors gamma-butyrolactone and 1,4-butanediol produced 80 to 100% GHB-appropriate responding, whereas other compounds such as morphine, naltrexone, cocaine, and haloperidol produced no more than 34%. Compounds interacting with GABA receptors produced different maximal levels of GHB-appropriate responding. For example, the GABA(A) agonist muscimol produced 3%; the GABA(A)-positive modulators diazepam, pentobarbital, and ethanol, and the GABA(B) agonist baclofen produced levels ranging from 54 to 73%; and the benzodiazepine antagonist flumazenil and inverse agonist Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]-benzodiazepine-3-carboxylate) both produced 96%. The putative GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) produced 70% GHB-appropriate responding. The GABA(B) antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) completely blocked the GHB-like DS effects of NCS-382 and baclofen at a dose of 56 mg/kg. CGP 35348 also blocked the DS effects of GHB, but incompletely and only at a dose of 560 mg/kg. Together, these results are consistent with a role for diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABA(A) receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABA(B) receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABA(B) receptor-mediated, GHB-like agonist activity.     

Barium toxicity and the role of the potassium inward rectifier current

Introduction. Barium is a stable divalent earth metal and highly toxic upon acute and chronic exposure. Barium is present in many products and involved in a number of industrial processes. Barium targets the potassium inward rectifier channels (IRCs) of the KCNJx gene family. Extracellular barium enters and strongly binds the potassium selectivity filter region resulting in blockade of the potassium conducting pore. IRCs are involved in numerous physiological processes of the human body and the most barium sensitive IRCs are highly expressed in all muscle types. Objective. Our purpose was correlate to the clinical outcome of acute barium poisoning in man to current knowledge on IRC function. Methodology. The primary literature search was performed using Medline, Scopus and Google Scholar using search terms “barium AND poisoning”; “barium AND intoxication”; “barium AND case report” and retrieved publications from 1945 through 2012. Additional case reports were retrieved based on the reference lists of the primary hits. Duplicate publications, or publications presenting identical cases were omitted. A total of 39 case reports on acute barium poisoning containing 226 human subjects were identified for review. Results. BaCO₃ was the most frequent source and food the most frequent mode of poisoning. Patients suffered from gastrointestinal (vomiting, diarrhea), cardiovascular (arrhythmias, hypertension), neuromuscular (abnormal reflexes, paralysis), respiratory (respiratory arrest/failure) and metabolic (hypokalemia) symptoms. Severe hypokalemia (< 2.5 mM) was observed from barium serum concentrations greater than or equal to 0.0025 mM. Review of the ECG outcomes demonstrated ventricular extrasystoles, ST changes and profound U-waves to be associated strongly with poisoning. Most common treatment modalities were gastric lavage, oral sulfates, potassium i.v. and cardiorespiratory support. 27 patients (12%) died from barium poisoning. Conclusions. Barium is a potent, non-specific inhibitor of the potassium IRC current and affects all types of muscle at micromolar concentrations. Gastrointestinal symptoms frequently occur early in the course of barium poisoning. Hypokalemia resulting from an intracellular shift of potassium and the direct effect of barium at the potassium channels explain the cardiac arrhythmias and muscle weakness which commonly occur in barium poisoning. Treatment of barium poisoning is mainly supportive. Orally administered sulfate salts to form insoluble barium sulfate in the intestinal tract and potassium supplementation have potential but unproven benefit.     

Novel gamma-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABAB receptor agonists

gamma-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA(B) receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA(B) receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace [(3)H]NCS-382 [5-[(3)H]-(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7] annulen-6-ylidene) ethanoic acid] from GHB receptors at concentrations that do not markedly affect [(3)H]GABA binding to GABA(B) receptors. In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (gamma-butyrolactone and 1,4-butanediol) and GABA(B) receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA(B) receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA(B) receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being mediated by GABA(B) receptors. Ataxia that was observed with UMB86, UMB72, UMB73, and 3-HPA was not antagonized by CGP35348, suggesting that ataxia induced by these analogs is not mediated by GABA(B) receptors and might involve GHB receptors.     

Epidemiology and clinical features of toxicity following recreational use of synthetic cannabinoid receptor agonists: a report from the United Kingdom National Poisons Information Service

Context: Toxicity from the use of synthetic cannabinoid receptor agonists (SCRAs) has been encountered increasingly frequent in many countries. Objective: To characterise presentation rates, demographic profiles and reported clinical features for users of SCRAs referred by health professionals in the United Kingdom to the National Poisons Information Service (NPIS), to compare reported toxicity between commonly used branded products, and to examine the impact of legal control measures on enquiry numbers. Methods: NPIS telephone enquiry records were searched for SCRA-related terms for the 8-year period 1st January 2007 to 31st December 2014, consolidating multiple enquiries about the same case into a single record. Demographic data, reported exposure details, clinical features and poisoning severity were analysed, excluding cases where SCRA exposure was unlikely. Results: Enquiries to the NPIS were made concerning 510 individuals relating to probable SCRA use, with annual numbers increasing year on year. Most patients were male (80.8%) and?<25 years old (65.1%). Common clinical features reported in the 433 (84.9%) patients reporting SCRA use without other substances included tachycardia (n?=?73, 16.9%), reduced level of consciousness (n?=?70, 16.2%), agitation or aggression (n?=?45, 10.4%), vomiting (n?=?30, 6.9%), dizziness (n?=?26, 6.0%), confusion (n=?21, 4.8%), mydriasis (n?=?20, 4.6%) and hallucinations (n?=?20, 4.6%). The Maximum Poisoning Severity Score (PSS) indicated severe toxicity in 36 cases (8.3%). Legal control of “second generation” SCRAs did not affect the rate of growth in enquiry numbers or the proportion with severe toxicity. The three most commonly reported products were “Black Mamba” (n=?88, 20.3%), “Pandora’s Box” (n=?65, 15.0%) and “Clockwork Orange” (n=?27, 6.2%). Neurological and general features were recorded more often with “Clockwork Orange” than for “Black Mamba” and “Pandora’s Box”, but moderate or severe toxicity was significantly less common after reported use of this product. Conclusions: Enquiries about SCRA-related toxicity have become increasingly frequent in the UK in spite of legal controls and commonly involve younger males. Differences in the patterns of toxicity associated with different branded preparations may occur, although further work with larger patient numbers is needed to confirm this.     

Case series of 226 γ-hydroxybutyrate–associated deaths: lethal toxicity and trauma

γ-Hydroxybutyrate (GHB) and its prodrugs are drugs of abuse that were also sold as “dietary supplements.” Users present to emergency departments with overdose, impaired driving, withdrawal, and associated trauma. We compiled a series of GHB-associated deaths to elucidate lethal risks, GHB concentrations, cointoxicants, products, uses, and medical interventions. Death records were reviewed for toxicology, autopsy findings, and history. Inclusion cutoffs were as follows: 5/10 mg/L of GHB (antemortem blood/urine) and 50/20/7 mg/L of GHB (postmortem blood/urine/vitreous). Of 226 deaths included, 213 had cardiorespiratory arrest and 13 had fatal accidents. Seventy-eight deaths (35%) had no cointoxicants. Sixteen deaths involved “supplements” and 1 involved pharmaceutical GHB (Xyrem, Jazz Pharmaceuticals, Palo Alto, CA). Postmortem blood GHB was 18 to 4400 mg/L (median, 347 mg/L) in deaths negative for cointoxicants. Cardiorespiratory arrest occurred prehospital in 100% of 184 cases with available history. Of 72 cases with antemortem adverse effects reported, medical assistance was delayed or absent in 66; of these, acute GHB ingestion was known in 51, including 40 left to “sleep off” adverse effects. Thirty others were left “sleeping” and found dead. γ-Hydroxybutyrate is lethal even without cointoxicants, directly and through fatal accidents. Medical interventions were frequently delayed or absent despite known GHB ingestion, and witnessed adverse events and cardiorespiratory arrest occurred prehospital. Education is needed about the lethality of GHB and the necessity for prompt medical intervention.     

Aseptic meningitis in association with glyphosate-surfactant herbicide poisoning

Introduction.?The mechanisms underlying early central nervous system (CNS) signs and symptoms of glyphosate-surfactant herbicide (GlySH) poisoning are unclear. Case presentation.?A 58-year-old woman ingested approximately 150 mL of GlySH containing 41% glyphosate and 15% polyoxyethyleneamine. Two days later, she was admitted in the Emergency Center in a semicomatose state. Acute respiratory distress syndrome, circulatory collapse, acute renal failure, and disseminated intravascular coagulopathy were diagnosed. Meningitis was also suspected as she demonstrated Kernig's sign and significant neck stiffness with rigidity of the extremities as well as consciousness disturbance and fever (38.4°C). Investigations of cerebrospinal fluid (CSF) revealed the presence of glyphosate (122.5?μg/mL), significant elevation of IL-6 (394?μg/mL), and pleocytosis (32 cells/μL) with monocyte dominance. All bacteriological and virological tests were later found to be negative. She recovered completely after responding to aggressive supportive care in the intensive care unit. All signs and symptoms suggesting meningitis resolved as the concentration of glyphosate in CSF decreased. She was discharged on day 39 of hospitalization. Discussion.?These findings suggest that the present case involved aseptic meningitis in association with GlySH poisoning. Conclusion.?CNS signs and symptoms induced by aseptic meningitis should be considered in cases of glyphosate-surfactant herbicide poisoning.     

Colchicine poisoning: the dark side of an ancient drug

Introduction. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. Methods. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included “colchicine” and “poisoning” or “overdose” or “toxicity” or “intoxication.” Toxicokinetics. Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. Therapeutic and toxic doses. The usual adult oral doses for FMF is 1.2–2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5–0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7–26 mg. Drug interactions. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Mechanisms of toxicity. Colchicine's toxicity is an extension of its mechanism of action – binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. Reproductive toxicology and lactation. Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Clinical features. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10–24 h after ingestion – gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion – multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. Diagnosis. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Management. Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Conclusion. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.