An investigation of flumazenil to antagonize gamma-hydroxybutyrate intoxication in a murine model

Lee, Dong Hoon; Satz, Wayne A.; Dougherty, Timothy; Greene, Tucker

doi:10.1007/bf03161174

Cited by 7 publications

(3 citation statements)

References 10 publications

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“…Many substances such as (naloxone, flumazemil, or GABA B antagonists have been tried as potential antidotes, but there is no sufficient scientific evidence to support their routine application ( 51 , 52 , 53 , 54 , 55 ).…”

Section: Acute Poisoning With Ghbmentioning

confidence: 99%

Gamma-hydroxybutyrate abuse: pharmacology and poisoning and withdrawal management

Marinelli

Beck

Malvasi

et al. 2020

Archives of Industrial Hygiene and Toxicology

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Gamma-hydroxybutyrate (GHB) is a central nervous system depressant primarily used as a recreational drug of abuse, but also for the treatment of narcolepsy with cataplexy in adult patients and as an adjuvant for control of alcohol withdrawal syndrome. The main aim of this review is to summarise updated knowledge about GHB pharmacokinetics and pharmacodynamics, acute poisoning, and clinical features of GHB withdrawal syndrome, its diagnosis and medical treatment. The most common clinical signs and symptoms of acute poisoning include sleepiness to deep coma, bradycardia, hypotension, and respiratory failure. Therapy is essentially supportive and based on continuous monitoring of vital signs. GHB withdrawal syndrome shares patterns with other withdrawal syndromes such as alcohol withdrawal and is sometimes difficult to distinguish, especially if toxicological tests are GHB-negative or cannot be performed. There are no official detoxification protocols for GHB withdrawal syndrome, but its therapy is based on benzodiazepine. When benzodiazepine alone is not effective, it can be combined with barbiturates or antipsychotics. Information about abuse and distribution of GHB and its precursors/analogues among the general population is still limited. Their prompt identification is therefore crucial in conventional and non-conventional biological matrices, the latter in particular, to clarify all the issues around this complex molecule.

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Section: Acute Poisoning With Ghbmentioning

confidence: 99%

Gamma-hydroxybutyrate abuse: pharmacology and poisoning and withdrawal management

Marinelli

Beck

Malvasi

et al. 2020

Archives of Industrial Hygiene and Toxicology

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“…In one study, physostigmine showed some promise in reversing GHB-induced altered states of consciousness [ 165 , 166 ], although its efficacy was later challenged [ 167 ]. Neither naloxone, a pure opiate antagonist [ 168 ], nor the selective benzodiazepine receptor antagonist flumazenil [ 169 ] were effective in reversing GHB sedation. A novel GABA-B antagonist was tested in mice as a way of lowering mortality caused by massive doses of GHB, but it did not seem to have any beneficial effects [ 170 ].…”

Section: Treatment Of Ghb Intoxicationmentioning

confidence: 99%

GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome

Busardò¹,

Jones²

2015

184

227

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The illicit recreational drug of abuse, γ-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem®), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover®) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t½ ~1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of ~100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from administering benzodiazepines.

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“…Representatively, physostigmine has shown the possibility of recovering the GHB-induced change in consciousness state [ 24 , 25 ]. However, physostigmine increases cardiovascular-related side effects [ 26 ], while naloxone [ 27 ], an opiate antagonist, and flumazenil [ 28 ], a selective benzodiazepine receptor antagonist, have not been found to be effective in reversing the sedative effects of GHB. Upon studying whether the γ-aminobutyric acid (GABA)-B receptor antagonist has an effect on reducing mortality due to excessive GHB intake in mice, no significant effect was found [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Alterations Associated with γ-Hydroxybutyric Acid and the Potential of Metabolites as Biomarkers of Its Exposure

et al. 2021

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γ-Hydroxybutyric acid (GHB) is an endogenous short chain fatty acid that acts as a neurotransmitter and neuromodulator in the mammalian brain. It has often been illegally abused or misused due to its strong anesthetic effect, particularly in drug-facilitated crimes worldwide. However, proving its ingestion is not straightforward because of the difficulty in distinguishing between endogenous and exogenous GHB, as well as its rapid metabolism. Metabolomics and metabolism studies have recently been used to identify potential biomarkers of GHB exposure. This mini-review provides an overview of GHB-associated metabolic alterations and explores the potential of metabolites for application as biomarkers of GHB exposure. For this, we discuss the biosynthesis and metabolism of GHB, analytical issues of GHB in biological samples, alterations in metabolic pathways, and changes in the levels of GHB conjugates in biological samples from animal and human studies. Metabolic alterations in organic acids, amino acids, and polyamines in urine enable discrimination between GHB-ingested animals or humans and controls. The potential of GHB conjugates has been investigated in a variety of clinical settings. Despite the recent growth in the application of metabolomics and metabolism studies associated with GHB exposure, it remains challenging to distinguish between endogenous and exogenous GHB. This review highlights the significance of further metabolomics and metabolism studies for the discovery of practical peripheral biomarkers of GHB exposure.

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An investigation of flumazenil to antagonize gamma-hydroxybutyrate intoxication in a murine model

Abstract: In this model, pre-dosing flumazenil prior to GHB administration delayed clinical intoxication.

Cited by 7 publications

References 10 publications

Gamma-hydroxybutyrate abuse: pharmacology and poisoning and withdrawal management

Gamma-hydroxybutyrate abuse: pharmacology and poisoning and withdrawal management

GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome

Metabolic Alterations Associated with γ-Hydroxybutyric Acid and the Potential of Metabolites as Biomarkers of Its Exposure

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