• Biomolecules & Therapeutics
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• v.7 no.3
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• pp.242-248
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• 1999

Diazepam, a benzodiazepine (BDZ) agonist, produces sedation and flumazenil, a BDZ antagonist, blocks these actions. The aim of this study was to examine the effects of BDZs on cortical electroencephalogram (EEG) in rats. The recording electrodes were implanted over the frontal and parietal cortices bilaterally, and the reference and ground electrodes over cerebellum under ketamine anesthesia. To assess the effects of diazepam and flumazenil, rats were injected with diazepam (1 mgHg, i.p.) and/or flumazenil ( 1 mg/kg, i.p.), and the EEG was recorded before and after drugs. Normal awake had theta peak in the spectrum and low amplitude waves, while normal sleep showed large amplitude of slow waves. The powers of delta, theta and alpha bands were increased during sleep compared with during awake. Diazepam reduced the mobility of the rat and induced sleep with intermittent fast spindles and large amplitude of slow activity, and it produced broad peak over betaL band and increased the power of gamma band, which were different from EEG patterns in normal sleep. Saline injection awakened rats and abolished fast spindles for a short period about 2-5 min from EEG pattern during diazepam-induced sleep. Flumazenil blocked both diazepam-induced sleep and decreased the slow activities of delta, theta, alpha and betaL, but not of gamma activity for about 10 min or more. This study may indicate that decrease in power of betaL and betaH bands can be used as the measure of central action of benzodiazepines, and that the EEG parameters of benzodiazepines have to be measured without control over the behavioral state by experimenter.

• Korean Journal of Psychosomatic Medicine
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• v.27 no.2
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• pp.111-118
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• 2019

Objectives : The purpose of this study was to investigate the clinical characteristics of antipsychotic medication prescription for the symptom control in patients with delirium. Methods : One hundred and eighty-five patients referred to consultation-liaison psychiatric services for delirium due to general medical condition were included in this study. All subjects were divided into two groups (antipsychotics users vs. antipsychotics nonusers), and comparison analyses on their clinical characteristics were performed. Results : One hundred and twenty nine patients (66.5%) used antipsychotics for their delirium, and 56 patients (30.3%) did not use antipsychotics. The history of psychotropic medication was more frequently observed in antipsychotic users (5.4% vs. 18.6%, χ²=5.498, p=0.022). Especially, the history of benzodiazepine use was significantly high in antipsychotics users. The total score and sub-items of delirium rating scale-severity items except for the psychomotor retardation item showed higher scores in antipsychotic users than in nonusers (all p<0.05). The total score of the delirium rating scale-diagnosis items was higher in antipsychotic users than in the nonusers (p=0.010). Conclusions : Delirium patients with more severe delirium symptoms and with more history of benzodiazepine use were treated with antipsychotics more frequently than those without. These findings imply that benzodiazepine may not only exacerbate delirium but be associated with aggression or psychomotor agitation that need immediate intervention. Clinicians may need to pay attention not only these external symptoms but also to hypoactive symptoms that may lead to misdiagnosis and undertreatment.

• Journal of Veterinary Clinics
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• v.27 no.4
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• pp.336-342
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• 2010

The purpose of this study was to determine the antagonistic effects of flumazenil on anesthesia induced with tiletamine/zolazepam in dogs. The anesthetic effects (sedation, analgesic, muscle relaxation, posture and auditory response score), vital signs (heart rate, respiratory rate and rectal temperature) and blood biochemistry (glucose (GLU), total protein (TP), alanine aminotransferase (ALT), aspartate aminotransferase (AST)) were examined as indicators of the antagonistic effects. A total of 6 clinically healthy mongrel dogs were used in this study. The dogs in TZ group received administration of tiletamine/zolazepam 10 mg/kg IV. The dogs in TZF group received administration dose of TZ 10 mg/ kg IV followed by the administration of flumazenil 0.1 mg/kg 20 minutes after administering a TZ 10 mg/kg dose. There were significant differences in the recovery of anesthesia between the groups. The GLU level in the TZF group after the administration of flumazenil was significantly higher than that of the TZ group. There was a larger change in the HR in the TZF group than in the TZ group until 30 minutes after flumazenil administration. The sternal recumbency, standing and walking times of the TZF group were faster than those of the TZ group. In conclusion, flumazenil showed antagonistic effect against tiletamine/zolazepam in dogs. When recovering from anesthesia, flumazenil reduced sternal recumbency, standing and walking times.

• The Korean Journal of Nuclear Medicine Technology
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• v.12 no.3
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• pp.176-180
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• 2008

Department of Nuclear Medicine in Seoul National University Hospital (SNUH) had developed $^{18}F$-Flumazenil as Benzodiazepine receptor imaging agent for PET diagnosis of Epilepsy. But production Activity of $^{18}F$-Flumazenil is decreased owing to this method has difficult synthesis procedures and pretty long synthesis time. In this study, we can modify synthesizing method to have more simple procedure and less spend time and help to increase production Activity. Old method: Radioactivity was produced by cyclotron was captured by QMA cartridge that was activated. Captured radioactivity was eluted into the reaction vial by using kryptofix solution and delivered. After evaporation of eluent, the azeotrophic drying step repeated two times. tosylflumazenil in anhydrous Acetonitrile was added to a reaction vial while bubbling. The reaction mixture was evaporated until the mixture volume was 0.5 mL. Reaction vial washed with 20 % Acetonitrile and that solution went into the reaction vial. The reaction mixture was loaded to the HPLC loop by hand and purified $^{18}F$-Flumazenil by HPLC column. New method: We used $TBAHCO_3$ solution as a eluent. After the eluent was evaporated, tosylflumazenil in anhydrous acetonitrile was added to a reaction vial and the reaction mixture was bubbled for 15 minutes. It was evaporated until the mixture volume became 0.5 mL. It was loaded to the HPLC loop. In old method, $^{18}F$-Flumazenil was synthesized via 6 steps synthesis procedures in 105 minutes with 30~35% synthesizing yield (non-decay correction) and specific activity was about $0.5{\sim}2{\times}10^5$ Ci/mole. In new method, It had 3 steps synthesis procedures in 53 minutes with 40~45% synthesizing yield and specific activity was about $3{\sim}8{\times}10^5$ Ci/mole. This method leads to improve of minimizing synthesis time, increasing synthesis yield and specific activity. While we can load reaction mixture to the HPLC loop, we can expose high radiation field thanks to used by hand.

• Proceedings of the Korean Society of Toxicology Conference
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• 2005.05a
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• pp.120-120
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• 2005

• Bulletin of the Korean Chemical Society
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• v.29 no.11
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• pp.2135-2139
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• 2008

• Proceedings of the PSK Conference
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• 2002.04a
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• pp.123.2-123.2
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• 2002

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.342.2-342.2
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• 2002

The ${\beta}$-turn has been implicated as an important conformation for biological recognition of peptides or proteins. Benzodiazepine classes have been known as one of the non peptide ${\beta}$-turn mimic scaffolds. We have developed an efficient approach for the synthesis and derivatization of a scaffold of hydroxytetrahydrodizepinone class in order to screen compound library in various protein targets for new lead generations as well as for structure activity relationships of the scaffold. (omitted)

• Journal of The Korean Society of Clinical Toxicology
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• v.14 no.2
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• pp.92-99
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• 2016

Purpose: The use of flumazenil administration in the emergency department is still controversial because of concerns about adverse effects. The present study was conducted to re-evaluate the risk-benefit ratio associated with flumazenil administration to patients suspected of having acute hypnotics and sedatives poisoning in the emergency department. Methods: A retrospective chart review study was conducted for patients whose final diagnoses were "poisoning" and "benzodiazepine" or "sedatives-hypnotics" from Mar. 2006 to Feb. 2015. The basal characteristics of the patients, including past medical history, ingredients and dose of ingested drug and co-ingested drugs were investigated. For patients administered flumazenil, responsiveness and time from admission to flumazenil administration were investigated with supplement. All collected data were analyzed in aspect terms of risk/benefit. Results: A total of 678 patients were included in our study. Benzodiazepine was the most common sedative/hypnotic drug prescribed, and the frequency of prescription continuously increased. The proportion of TCA as co-ingestion decreased from 13.1% to 3.9% in patients with acute sedative/hypnotic poisoning. Flumazenil was administered to 55 patients (8.1%), of which 29 patients (52.7%) were applied to contraindications. Fifty-three patients (96.4%) showed positive responsiveness, including partial responsiveness after flumazenil administration. No severe adverse events were identified. Conclusion: Based on the current trends in prescription patterns for sedative/hypnotic drugs, increased use of non-TCA antidepressants, and responsiveness to administration of flumazenil, benefit seemed weighted more in this study, although the observed benefits were based on limited results. Further prospective multicenter studies will be needed to optimize benefit-risk ratio.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.5
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• pp.555-563
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• 1998

The renal function is under regulatory influence of central nervous system (CNS), in which various neurotransmitter and neuromodulator systems take part. However, a possible role of central GABA-benzodiazepine system on the central regulation of renal function has not been explored. This study was undertaken to delineate the renal effects of diazepam. Diazepam, a benzodiazepine agonist, administered into a lateral ventricle (icv) of the rabbit brain in doses ranging from 10 to 100 ${\mu}g/kg,$ elicited dose-related diuresis and natriuresis along with improved renal hemodynamics. However, when given intravenously, 100 ${\mu}g/kg$ diazepam did not produce any significant changes in all parameters of renal function and systemic blood pressure. Diazepam, 100 ${\mu}g/kg$ icv, transiently decreased the renal nerve activity (RNA), which recovered after 3 min. The plasma level of atrial natriuretic peptide (ANP) increased 7-fold, the peak coinciding with the natriuresis and diuresis. Muscimol, a GABAergic agonist, 1.0 ${\mu}g/kg$ given icv, elicited marked antidiuresis and antinatriuresis, accompanied by decreases in systemic blood pressure and renal hemodynamics. When icv 0.3 ${\mu}g/kg$ muscimol was given 3 min prior to 30 ${\mu}g/kg$ of diazepam icv, urinary flow and Na excretion rates did not change significantly, while systemic hypotension was produced. These results indicate that icv diazepam may bring about natriuresis and diuresis by influencing the central regulation of renal function, and that the renal effects are related to the increased plasma ANP levels, not to the decreased renal nerve activity, and suggest that the effects may not be mediated by the activation of central GABAergic system.