• Journal of the korean academy of Pediatric Dentistry
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• v.29 no.2
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• pp.159-167
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• 2002

The purpose of this study was to evaluate the efficacy and safety depending on the route of flumazenil, as an antagonist against midazolam. The subjects of this study were 15 volunteers of $22{\sim}24$ years old. They were sedated with midazolam 0.2mg/Kg intranasal spray, and then 40 minutes after midazolam administration, they were given flumazenil 0.2mg intranasal spray for their reversal. For evaluation of the efficacy and safety of intranasal spray for flumazenil, they were monitored with pulse-oxymeter(Nellcor symphony N-3000, Nellcor Puritan CO. USA) and electric sphygmomanometer (Heartcare 200, National CO. Japan), and were assessed themselves using visual analogue scale(VAS) for tranquilization, sleep, fatigue and attitude. All of these subjects were reduced completely without any undesired situations. The results from this study can be summarized as follows ; 1. Nasaly administered flumazenil using spray device produced much more rapid reduction than intravenously administered flumazenil, but soon after fell in more deep sedated state than intravenously administered flumazenil. 2. There were no considerable side effects or bad influence on vital signs of both nasaly administered flumazenil and intravenously administered flumazenil. These results suggested that the flumazenil administered nasaly using spray device for reversal, we could treat patients safely and effectively under conscious sedation using midazolam administration. But, We will have to research about its optimal dosages for flumazenil, used as intranasal spray for reversal agents against the midazolam by evaluating the blood plasma concentration of midazolam and flumazenil.

• Journal of the korean academy of Pediatric Dentistry
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• v.32 no.3
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• pp.499-508
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• 2005

The purpose of this study were to evaluate the effect on the reversion of sedation induced by midazolam with flumazenil and to determine the plasma concentration of flumazenil according to the method of administration. Intranasal and intravenous flumazenil were administered to sedated health volunteers aged from 23 to 25 years, in doses typical of those used clinically to induce sedation with midazolam and for reversal with flumazenil. Objective assessment for degree of sedation and vital signs, plasma concentration were made for 2 hours period. 1. Systolic and diastolic blood pressure, $SpO_2$ were not changed by adminstration of flumazenil in sedated subject with midazolam, but pulse rate was increased temporarily. 2. Flumazenil showed the reversal of the sedative effect induced by midazolam regardless of administration methods. But intravenous administration showed more effect on the degree and the duration of reversion than intranasal administration with the exception of on set time. 3. Peak plasma concentration of flumazenil administered by intranasal route reached after 2 min and that of flumazenil administered by intravenous route was 4 min. Thus uptake of flumazenil did not showed any difference in accordance with the adminstration route. 4. Administration of flumazenil resulted in the temporary increase of midazolam plasma concentration.

• 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
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• v.33 no.6
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• pp.527-536
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• 1999

Purpose: Radiotracers that bind to the central benzodiazepine receptor are useful for the investigation of various neurological and psychiatric diseases. [C-11]Flumazenil, a benzodiazepine antagonist, is the most widely used radioligand for central benzodiazepine receptor imaging by PET. We synthesized 3-(2-[F-18]fluoro)flumazenil, a new fluorine-18 ($t_{1/2}$= 110 min) labeled analogue of benzodiazepine receptor imaging agent, and evaluated in vivo for biodistribution in mice. Materials and Methods: Flumazenil (Ro 15-1788) was synthesized by a modification of the reported method. Precursor of 3-(2-[F-18]fluoro)flumazenil, the tosylated flumazenil derivative was prepared by the tosylation of the ethyl ester by ditosylethane. [F-18] labeling of tosyl substitued flumazenil precursor was performed by adding F-18 ion at $85^{\circ}C$ in the hot ceil for 20 min. The reaction mixture was trapped by C18 cartridge, washed with 10% ethanol, and eluted by 40% ethanol. Bidistribution in mice was determined after intravenous injection. Results: The total chemical yield of tosylated flumazenil derivative was ${\sim}40%$. The efficiency of labeling 3-(2-[F-18]fluoro)flumazenil was 66% with a total synthesis time of 50 min. Brain uptakes of 3-(2-[F-18]fluoro)flumazenil at 10, 30, 60 min after injection, were $2.5{\pm}0.37,\;2.2{\pm}0.26,\;2.1{\pm}0.11$ and blood activities were $3.7{\pm}0.43,\;3.3{\pm}0.07,\;3.3{\pm}0.09%ID/g$, respectively. Conclusion: We synthesized a tosylated flumazenil derivative which was successfully labeled with no-carrier-added F-18 by nucleophilic substitution.

• 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.

• 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.

• Journal of the korean academy of Pediatric Dentistry
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• v.28 no.3
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• pp.441-446
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• 2001

Flumazenil is a competitive antagonist of benzodiazepines. It is usually administered intravenously. However, if the intravenous route is not available then other routes of drug administration should be considered. This study was designed to evaluate the reversal effects of flumazenil after nasal administration. Twenty-five young, healthy adult volunteers participated in this clinical trial. The dosage of 0.08mg/kg midazolam was administered intravenously to induce deep sedation. Ten minutes after midazolam administration, 0.5mg of flumazenil was dropped nasally, over a period of one minute. Blood samples were taken to measure the concentration of midazolam and flumazenil at 0, 5, 10, and 20min after nasal administration of flumazenil, using High Performance Liquid Chromatography. The degree of sedation was evaluated with sedation score and bispectral index (BIS), Statistical analysis was performed by multivariate ANOVA and correlation analysis (P<0.05). Peak serum flumazenil concentration was reached in 10min. Sedation score decreased after midazolam administration and showed a significant increase after flumazenil administration. However, BIS decreased during the first 10min after midazolam administration and then no significant changes after flumazenil administration. There were two instances representing rapid and complete reversal of midazolam after intranasal administration of flumazenil. In conclusion, intranasal flumazenil administration may be effective in some patients when intravenous route is not available in condition of benzodiazepine overdose.

• Archives of Pharmacal Research
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• v.28 no.2
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• pp.238-242
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• 2005

Many reports demonstrate that extremely low frequency magnetic fields (ELF MFs, 60 Hz) may be involved in hyperalgesia. In a previous investigation, we suggested that MFs may produce hyperalgesia and such a response may be regulated by the benzodiazepine system. In order to further confirm this effect of MFs, we used diazepam and/or flumazenil with MFs exposure. When testing the pain threshold of rats using hot plate tests, MFs or diazepam ($0.5\;{\mu}g$, i.c.v.; a benzodiazepine receptor agonist) induced hyperalgesic effects with the reduction of latency. These effects were blocked by a pretreatment of flumazenil (1.5 mg/kg, i.p.; a benzodiazepine receptor antagonist). When the rats were exposed simultaneously to MFs and diazepam, the latency tended to decrease without statistical significance. The induction of hyperalgesia by co-exposure to MFs and diazepam was also blocked by flumazenil. However, the pretreatment of GABA receptor antagonists such as bicuculline ($0.1\;{\mu}g$, i.c.v.; a $GABA_A$ antagonist) or phaclofen ($10\;{\mu}g$, i.c.v.; a $GABA_B$ antagonist) did not antagonize the hyperalgesic effect of MFs. These results suggest that the benzodiazepine system may be involved in MFs-induced hyperalgesia.

• Journal of Physiology & Pathology in Korean Medicine
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• v.35 no.1
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• pp.8-14
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• 2021

Shihogayonggolmoryo-tang (ST) is a Korean medical herb cocktail which has been used to treat anxiety induced insomnia. In this study, we will examine sleep-promoting and anti-anxiety effects of ST, and investigate its mechanism. ICR mice were divided into three groups for the first examination : control group (n=11), ST50 group (50 mg/kg, po, n=11), ST200 group (200 mg/kg, po, n=11). Sleep-promoting effect was confirmed by measuring the sleeping duration time and sleeping onset time after thiopental sodium treatment (50 mg/kg, ip). ICR mice were divided into five groups for the second examination : control group (n=11), ST200 group (200 mg/kg, po, n=11), ST200+Flumazenil group (ST 200 mg/kg, po, flumazenil 0.3 mg/kg, ip, n=11), diazepam group (1 mg/kg, ip, n=11), diazepam+flumazenil group (diazepam 1 mg/kg, ip, Flumazenil 0.3 mg/kg, ip, n=11). Anxiety behavior and sleep-promoting effect was confirmed by open field test and measuring the sleeping duration time and sleeping onset time. Expression levels of c-fos in tuberomammillary nucleus (TMN) and ventrolateral preoptic nucleus (VLPO) were analyzed by immunohistochemistry. ST treated group showed significantly decreased anxiety behavior and enhanced sleeping duration time and sleeping onset time concentration dependently. The expression of c-fos was significantly upregulated in VLPO as sleep-inducing center and TMN as downregulated in arousal center by ST treatment. In addition, all effects of ST were reversed by flumazenil. Our results suggest that ST has sleep-promoting and anti-anxiety effects through regulating arousal center (TMN) and sleep-inducing center (VLPO).

• 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.