Adverse Events, Including Death, Associated with the Use of 1,4-Butanediol

Zvosec, Deborah L.; Smith, Stephen W.; McCutcheon, J. Rod; Spillane, Joe; Hall, Bradley J.; Peacock, Elizabeth A.

doi:10.1056/nejm200101113440202

Cited by 208 publications

(152 citation statements)

References 29 publications

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“…These results support the hypothesis that GHB acts preferentially at the level of the hippocampus to inhibit information processing. The present results may help explain why individuals intoxicated with GHB may not remember specific experiences due to disruptions in hippocampal processing but have intact emotional memories [4,68]. Whether GHB impairs hippocampusbased cognitive functioning in male adolescent rat needs to be investigated.…”

Section: Discussionmentioning

confidence: 86%

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Sircar

Ishiwari²

2014

Journal of Drug and Alcohol Research

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γ-hydroxybutyric acid (GHB) causes retrograde amnesia in juveniles and young adults. Earlier, we have reported that in adolescent rat, GHB impairs the hidden platform task performance in the Morris water maze. In the present study, a classical fear conditioning paradigm was used to examine the effects of GHB on the acquisition of contextual conditioning, a hippocampus-dependent associative task, and cued tone conditioning, a hippocampus-independent task, in adolescent rats. Administration of GHB before the presentation of tone-shock pairings dose-dependently disrupted the acquisition of contextual conditioning with no effect on tone conditioning, when conditioned fear was measured 24 h later. Administering GHB prior to testing did not disrupt either contextual or tone conditioning. These results demonstrate that in the adolescent rat exposure to GHB preferentially disrupt hippocampal-dependent learning.

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Section: Discussionmentioning

confidence: 86%

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Sircar

Ishiwari²

2014

Journal of Drug and Alcohol Research

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“…The copolymer PK4 has faster hydrolysis kinetics than PK3; however it degrades into 1,4-butanediol, which is converted into γ-hydroxybutyrate in vivo, and subsequently causes toxicity to the central nervous system (15). Microparticles were formulated from PK3, using a solvent evaporation procedure.…”

Section: Resultsmentioning

confidence: 99%

Polyketal Copolymers: A New Acid-Sensitive Delivery Vehicle for Treating Acute Inflammatory Diseases

et al. 2008

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Acute inflammatory diseases are a major cause of death in the world, and effective treatments are greatly needed. Macrophages play a central role in causing acute inflammatory diseases, and there is currently great interest in developing drug delivery vehicles that can target therapeutics to macrophages. Microparticles formulated from aliphatic polyketals have great potential to enhance the treatment of acute inflammatory diseases, due to their ability to passively target therapeutics to macrophages, their acid sensitivity, and their biocompatible degradation products. However, existing aliphatic polyketals are unsuitable for treating acute inflammatory diseases because they require weeks to hydrolyze, and strategies for accelerating their hydrolysis kinetics are greatly needed. In this report we demonstrate that the hydrolysis kinetics of aliphatic polyketals can be accelerated by increasing their hydrophilic/hydrophobic balance. Aliphatic polyketals of varying hydrophobicity were synthesized, via the acetal exchange reaction, and their hydrolysis kinetics were investigated at the pH values of 4.5 and 7.4. A polyketal termed PK3 was developed, which had the hydrolysis kinetics suitable for treating acute inflammatory diseases. PK3 has a hydrolysis half-life of 2 days at pH 4.5, but requires several weeks to hydrolyze at pH 7.4. Microparticles were formulated with PK3, which encapsulated the anti-inflammatory drug, imatinib. In vivo experiments demonstrated that PK3 microparticles were able to significantly improve the efficacy of imatinib in treating acute liver failure. We anticipate that aliphatic polyketals will have numerous applications for the treatment of acute inflammatory diseases, given their pH sensitivity, tunable hydrolysis kinetics, and biocompatible degradation products.

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“…One explanation for the apparently high frequency of accidental GHB overdose (ie a greater level of sedation than intended, sometimes resulting in medical intervention), even among experienced users (Miotto et al, 2001;Degenhardt et al, 2002Degenhardt et al, , 2003, is the variability of volume, concentration, and identity of GHB solutions on the street (eg GHB precursors or analogs are sold as substitutes for GHB; Zvosec et al, 2001), which makes it difficult to estimate a desired dose for self-administration (Degenhardt et al, 2003). In this study, known doses of GHB were administered on a weight-adjusted basis and under controlled conditions, thereby eliminating the aforementioned sources of variability and the possibility of cointoxicants.…”

Section: Discussionmentioning

confidence: 99%

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Carter

Richards

Mintzer

et al. 2006

Neuropsychopharmacol

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Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.

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Adverse Events, Including Death, Associated with the Use of 1,4-Butanediol

Abstract: 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.

Cited by 208 publications

References 29 publications

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Polyketal Copolymers: A New Acid-Sensitive Delivery Vehicle for Treating Acute Inflammatory Diseases

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

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