Confirmed glyburide poisoning from ingestion of "street Valium"

Background

Pharmaceuticals with little to no abuse potential are often sold surreptitiously as drugs of abuse on the street. Anecdotally, sulfonylureas are suspected to be commonly sold as “street Valium.”

Case Reports

Two patients presented with altered mental status and persistent hypoglycemia requiring continuous intravenous dextrose, in the context of suspected attempted benzodiazepine abuse. Supratherapeutic glyburide levels of 1198 and 647 ng/mL were measured in these patients.

Conclusions

These are two cases of glyburide poisonings from ingestion of “street Valium” that have been confirmed by laboratory testing.     

Anxiolytic effects of the melatonin MT2 receptor partial agonist UCM765: Comparison with melatonin and diazepam

Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT₁ and MT₂. However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT₂-selective partial agonist, UCM765 to evaluate the involvement of MT₂ receptors in anxiety. Adult male rats were acutely injected with UCM765 (5–10–20 mg/kg), MLT (20 mg/kg) or diazepam (DZ, 1 mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10 mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10 mg/kg) or MLT (20 mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1 mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT₁/MT₂ antagonist luzindole (10 mg/kg) or the MT₂ antagonist 4P-PDOT (10 mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT₂-receptors may be considered a novel target for the development of anxiolytic drugs.     

Sex differences in baseline and drug-induced behavioural responses in classical behavioural tests

Behavioural pharmacology relies on animal models which are primarily validated using the male laboratory rat. Many researchers solely employ male animals in studies; this is primarily due to concerns about the impact of variations in the female estrous cycle on behavioural responses. The objective of the present study therefore was to examine whether sex has any effect in some commonly employed behavioural pharmacology tests. Male and female Sprague Dawley rats were examined in the following behavioural pharmacology tests: diazepam (DZP) effects on anxiolytic behaviour in the elevated plus maze (EPM); desipramine (DMI) effects on immobility time in the forced swim test (FST); amphetamine (AMP) and apomorphine (APO) effects on locomotor activity in the homecage monitoring apparatus (HCMA). Baseline investigations revealed that females were more active than males in all three tests. DZP increased open arm time and entries for males but not for females. Similarly, significant reduction in immobility time with DMI was found for males in the FST, with no effect observed in females. There was a significant effect of AMP dose on distance moved for both sexes; the peak locomotor stimulating effects were seen following 1–2 mg kg^− 1 AMP doses for males, while 0.5 mg kg^− 1 produced the greatest effect in females. APO impaired locomotor activity in both sexes. These results demonstrate that male and female rats respond differently to psychotropic drugs. The absence of female responses to the effects of DZP and DMI in the EPM and FST respectively was due to the high baseline activity levels seen with females; thus behavioural tests must be designed to account for sex differences in baseline behaviours to allow for unambiguous extrapolation of the results.     

Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy

On the basis of our previous studies and the important role of the thalamo‐cortical network in states of unconsciousness, such as anaesthesia and sleep, and in sleep spindles generation, we investigated sleep spindles (SS) and high‐voltage sleep spindle (HVS) dynamics during non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep following different types of general anaesthesia in both physiological controls and in a rat model of Parkinson's disease (PD) cholinopathy, to follow the impact of anaesthesia on post‐anaesthesia sleep at the thalamo‐cortical level through an altered sleep spindle dynamics. We recorded 6 hr of spontaneous sleep in all rats, both before and 48 hr after ketamine/diazepam or pentobarbital anaesthesia, and we used 1 hr of NREM or REM sleep from each to validate visually the automatically detected SS or HVS for their extraction and analysis. In the controls, SS occurred mainly during NREM, whereas HVS occurred only during REM sleep. Ketamine/diazepam anaesthesia promoted HVS, prolonged SS during NREM, induced HVS of increased frequency during REM, and increased SS/HVS densities during REM versus NREM sleep. Pentobarbital anaesthesia decreased the frequency of SS during NREM and the HVS density during REM sleep. Although the pedunculopontine tegmental nucleus lesion prolonged SS only during NREM sleep, in these rats, ketamine/diazepam anaesthesia suppressed HVS during both sleep states, whereas pentobarbital anaesthesia promoted HVS during REM sleep. The different impacts of two anaesthetic regimens on the thalamo‐cortical regulatory network are expressed through their distinct sleep spindle generation and dynamics that are dependent on the NREM and REM state regulatory neuronal substrate.     

苯二氮类药物对细胞免疫功能的影响

苯二氮类药物（安定）能促进小鼠胸腺细胞增殖,这种作用以安定5mg/kg腹腔注射,每天一次连续给药5d的作用最强。安定对小鼠脾脏细胞增殖、自然杀伤（NK）细胞毒活性、脾细胞初次抗体产生以及对体外培养胸腺细胞增殖等均无明显影响。安定对截肢应激所致小鼠胸腺、脾脏细胞免疫抑制有拮抗作用,并可有效地拮抗应激导致的小鼠胸腺重量减轻。     

Effect of diazepam on reactivity of hippocampal neurons during blockade of the GABA-ergic system

Bulletin of Experimental Biology and Medicine -     

Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk

Background: The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.

Research design and methods: Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.

Results: Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R² = 0.239, p = 0.018; R² = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R² = 0.347, p = 0.026, R² = 0.513, p = 0.009).

Conclusions: The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.     

加味酸枣仁汤联合地西泮治疗焦虑性失眠的临床研究

[目的]探讨加味酸枣仁汤联合地西泮治疗焦虑性失眠的临床疗效。[方法]选择2016年1月—2018年5月本院收治的100例焦虑性失眠患者,随机分为对照组(50例)和研究组(50例)。对照组给予地西泮治疗,研究组给予加味酸枣仁汤联合地西泮治疗,两组均给予治疗4周。评价并比较两组临床疗效。比较两组治疗前后的汉密尔顿焦虑量表(HAMA)评分、焦虑自评量表(SAS)评分、匹兹堡睡眠质量指数量表(PSQI)评分及血清多巴胺(DA)、5-羟色胺(5-HT)、肿瘤坏死因子-α(TNF-α)水平及外周血CD4+、CD8+水平和CD4+/CD8+比值。[结果]研究组的总有效率为94.00%(47/50),对照组为76.00%(38/50),两组比较差异有统计学意义(χ2=6.353,P=0.012)。治疗后,两组HAMA评分、SAS评分及PSQI评分均明显低于治疗前,且研究组HAMA评分、SAS评分及PSQI评分的变化幅度均明显大于对照组(P0.05)。治疗后,两组血清DA、5-HT水平及外周血CD4+水平、CD4+/CD8+比值均明显高于治疗前,血清TNF-α水平和外周血CD8+水平均明显低于治疗前,且研究组血清DA、5-HT、TNF-α水平及外周血CD4+、CD8+水平、CD4+/CD8+比值的变化幅度均明显大于对照组(P0.05)。[结论]加味酸枣仁汤联合地西泮能够明显改善睡眠,减轻焦虑情绪,调节机体神经递质水平,纠正细胞免疫功能紊乱,且安全性较好。     

Use of an emergency sedation protocol to assist intubation in helicopter patient retrieval in Victoria

Abstract Objectives: To review emergency sedation intubation as practised in the Melbourne-based ambulance helicopter. Specifically, to describe patient profiles, drug dosage, difficulties encountered, success rate and patient outcomes. Methods: Retrospective review of all helicopter primary and secondary retrieval patients, who received application of the emergency sedation intubation protocol using morphine and diazepam during a 3 year period (January 1995 to December 1997). Data were collected from an audit of patient care records completed by flight paramedics and from hospital records. Results: Emergency sedation intubation was performed on 128 patients: 103 adults and 25 children. The median dose of drugs required for emergency sedation intubation by adult patients was 20 mg morphine and 20 mg diazepam. The overall success rate for emergency sedation intubation was 94.5%, with 73.6% of these being successful intubations at the first attempt. On intubation, 54.1% of patients were fully relaxed, while a gag reflex was still present in 45.9% of patients during or just after emergency sedation intubation. Twenty-two per cent of patients had a change in blood pressure of more than 20 mmHg. The maximum rise in blood pressure was 60 mmHg and the maximum fall was 80 mmHg. Conclusions: Flight paramedics achieved a high success rate for intubation with the morphine/ diazepam emergency sedation intubation protocol. However, there was still a significant percentage of patients for whom more than one attempt was required to achieve emergency sedation intubation and, in almost half the patients, gag reflexes remained present either during or immediately after intubation. Additionally, some patients experienced blood pressure changes following intubation that may have potential adverse consequences in terms of compromised cerebral perfusion or rises in intracranial pressure. Consideration should be given to revision of the protocol to allow the use of neuromuscular blocking agents and alternative airway management techniques, such as cricothyroidotomy, for specified circumstances in the aeromedical environment.