The protective effect and mechanism of diazepam on ischemia neurons during cerebral ischemia and reperfusion were studied. Sixty three Wistar rats were divided randomly into nine groups: control group , ischemia group...The protective effect and mechanism of diazepam on ischemia neurons during cerebral ischemia and reperfusion were studied. Sixty three Wistar rats were divided randomly into nine groups: control group , ischemia groups including subgroups of is3h, is3 h/rep1 h, is3 h/rep2 h, is3 h/rep3 h, diazepam treated groups , including subgroups of is3 h, is3 h/rep1 h, is3 h/rep2 h, is3 h/rep3 h with Zea longa’s animal model of middle cerebral artery occlusion. The comparison between the ischemia group and diazepam treated group showed that diazepam could obviously decrease the production of glutamate, asparate, MDA and increase the synthesis and release of GABA, SOD and GSH PX. It was concluded that diazepam exerted its protective effects on neurons through complex mechanisms of regulating the synthesis and release of excitotary/inhibitory amino acids and free radicals.展开更多
The solubility enhancement of diazepam and nitrazepam in water was analyzed depending on temperature and amount of α-cyclodextrin ( α-CD), β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). Th...The solubility enhancement of diazepam and nitrazepam in water was analyzed depending on temperature and amount of α-cyclodextrin ( α-CD), β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The interactions of drug-cyclodextrin in solution were investigated by the phase-solubility analysis. Diazepam (nitrazepam) content in aqueous complexation medium was analyzed UV spectrophotometrically. Classical solubility data were used to derive apparent stability constants (K1:1) which were used to derive thermodynamic parameters for the diazepam (nitrazepam)-cyclodextrin complexes. Since all phase solubility plots were of AL–types, and calculated Slopes after linear regression analysis were found to be less than 1, it could be assumed that stoichiometry of the formed binary systems was 1:1. According to the calculated K1:1 values, the stability of the complexes of diazepam and nitrazepam with a-CD, β-CD and 2-HP-β-CD varies as follows: 2-HP-β-CD > β-CD > β-CD. The a-CD has higher affinity for dissolving nitrazepam compared to diazepam. While all parameters lead to an improvement in solubility, the largest effect was obtained for guest-host complexation with 2-HP-β-CD. The solubility of diazepam and nitrazepam in water increased 93.02 times and 64.23 times, respectively, in the presence of 40% (w/w) 2-HP-β-CD, at 25°C. Solubility data for diazepam and nitrazepam in aqueous 2-HP-b-CD were used to derive thermodynamic parameters, ΔG° at 298 K = –14.43 kJ·mol–1, ΔH° = 0.79 kJ·mol–1, ΔS° at 298 K = 51.17 J·mol–1·K–1 and ΔG° at 298 K = –13.43 kJ·mol–1, ΔH° = 2.38 kJ·mol–1, ΔS° at 298 K = 53.01 J·mol–1·K–1, respectively. Formation of inclusion complexes substantially increases the water solubility of diazepam and nitrazepam. Diazepam and nitrazepam dissolution thermodynamics in aqueous 2-HP-β-CD were characterized by spontaneous and endothermic dissolution and hydrophobic interactions.展开更多
OBJECTIVE Investigate the effects of diazepam(DZP) on γ2 subunit containing GABA type A receptor(GABA A R) trafficking.METHODS Immunofluorescence microscopy measured surface GABA A Rs and gephyrin in rat cortical neu...OBJECTIVE Investigate the effects of diazepam(DZP) on γ2 subunit containing GABA type A receptor(GABA A R) trafficking.METHODS Immunofluorescence microscopy measured surface GABA A Rs and gephyrin in rat cortical neurons after 24 h exposure of 1.0 μmol·L^(-1) DZP.Biochemical studies of mice injected with 10 mg·kg^(-1) DZP vs vehicle were assessed for γ2 subunit and total gephyrin cortical levels 12 h post-injection.Ubiquitination of the γ2 subunit was studied by immunoprecipitation after 12 h of 1.0 μmol·L^(-1) DZP exposure.A γ2 subunit encoding an N terminal fluorogen-activating peptide and pH-sensitive green fluorescent protein(γ2 pH FAP) measured lysosomal targeting of γ2 containing GABA A Rs.RFP-gephyrin and γ2 pH FAP synaptic diffusion rates were examined using fluorescence recovery after photobleaching(FRAP).RESULTS Extrasynaptic levels of γ2 GABA A Rs decreased by 12.2%,while synaptic gephyrin S270 phosphorylation increased by 18.3% in DZP-treated neurons after 24 h compared to control(P<0.05).Dendritic levels of gephyrin were also reduced to 74.1% of control,while S270 phosphorylation was elevated by 25.2%(P<0.05;P<0.01).Mice 12 h post-DZP injection demonstrated a 12.7% and 26.1% decrease in total γ2 and gephyrin levels,respectively(P<0.05;P<0.01).12 h DZP treatment enhanced γ2 subunit ubiquitination 1.13-fold relative to control(P<0.05).Internalized γ2 pH FAP GABA A Rs associated with lysosomes was 8.0% higher in neurons treated with 12-16 h DZP compared to control.Pilot FRAP experiments suggest gephyrin and γ2 have increased mobility and turnover at synapses following DZP.CONCLUSION DZP treatment decreases γ2 GABA A R levels and gephyrin scaffolding function after one day of exposure,which may contribute to the formation of DZP tolerance.展开更多
AIM:To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias.METHODS:Between February 2002 and December 2009,a total of...AIM:To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias.METHODS:Between February 2002 and December 2009,a total of 286 patients with gastric epithelial neoplasia underwent endoscopic submucosal dissection in our hospital.To achieve moderate sedation,5-7.5 mg of diazepam was administered intravenously by non-anesthesiologists.Intermittent additional administration of 2.5-5 mg diazepam was performed if uncontrollable body movement of the patient was observed.All patients were classified into groups based on the required diazepam dose:low-dose (≤ 17.5 mg,n=252) and high-dose (> 17.5 mg,n=79).RESULTS:Differences between the low-and highdose diazepam groups were observed in lifetime alcohol consumption (0.30 ± 0.48 vs 0.44 ± 0.52 tons,P=0.032),body weight (58.4 ± 10.3 vs 62.0 ± 9.9 kg,P=0.006),tumor size (15 ± 10 vs 23 ± 18 mm,P < 0.001),lesion location (P < 0.001) and the presence of ulcerative findings (14/238 vs 18/61,P < 0.001).Multivariate analysis identified all five variables as independently related to required diazepam dosage.In terms of adverse reactions to diazepam administration,paradoxical excitement was significantly more frequent in the high-dose diazepam group (P < 0.001).CONCLUSION:Intermittent administration of diazepam enabled safe completion of gastric endoscopic submucosal dissection except in patients who were alcohol abusers or obese,or who showed complicated lesions.展开更多
Recent studies have shown the importance of the GABA-ergic transmission in the pathophysiology of anxiety and depressive disorders in humans. Our present study aims to investigate the interaction of melatonin (MEL) wi...Recent studies have shown the importance of the GABA-ergic transmission in the pathophysiology of anxiety and depressive disorders in humans. Our present study aims to investigate the interaction of melatonin (MEL) with this system by exploring the effects of MEL with or without a facilitator of GABA-ergic neurotransmission, diazepam (DZ) on the levels of depression and anxiety in Wistar rats. For this purpose, different doses of MEL (2, 4 or 16 mg/kg) or DZ (2 mg/kg) are subchronically administered during 15 days. After pharmacological treatments, anxiety levels are evaluated in behavioral tests of Open Field (OFT) and elevated plus maze (EPM) and depression levels are evaluated by the forced swim test (FST). The results showed that MEL produces anxiolytic-like and antidepressant-like effects in a dose-dependent manner;the maximum effect was obtained at a dose of 16 mg/kg. However, a dose of 4 mg/kg is necessary to induce an effect. The effect of MEL and DZ reported in this study concerns selective modulation of behavioral anxiety and depression since locomotor activity assessed by the OFT and EPM was not affected. The subchronic injection of MEL at 4 mg/kg, DZ at 2 mg/kg or the two combined molecules also induces also anxiety-like and antidepressant-like behavior. In addition, a potentiating effect between MEL and DZ was observed. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to improve the central GABA-ergic transmission.展开更多
Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, d...Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.展开更多
The present study analyzed expressional changes of excitatory neurotransmitters and inhibitory neurotransmitters in the rat corpus striatum after single-use and combined-use diazepam and Chinese herb moschus. The infl...The present study analyzed expressional changes of excitatory neurotransmitters and inhibitory neurotransmitters in the rat corpus striatum after single-use and combined-use diazepam and Chinese herb moschus. The influence of moschus on the central nervous system was analyzed, in particular whether moschus increased penetration of other drugs into the brain. Reverse-phase high-performance liquid chromatography, which included pre-column derivation with orthophthaladehyde detection, showed varied increased levels of excitatory neurotransmitters, including aspartate and glutamate, and inhibitory neurotransmitters, including glycine and Y-aminobutyric acid, in the corpus striatum after treatment with moschus alone, diazepam alone, or a combination of both. Compared with the diazepam group, aspartate levels significantly decreased at 30 and 60-105 minutes after combined treatment with moschus, while glutamate significantly increased at 45 and 75-105 minutes, glycine levels significantly increased at 105 minutes, and γ-aminobutyric acid increased at 30 and 75-105 minutes. These findings suggested that moschus increased the inhibition effects of diazepam on the brain.展开更多
AIM: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP ) 2C19 genotypes after an infusion regimen of diazepam commonly used forgastrointestinal endoscopy in...AIM: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP ) 2C19 genotypes after an infusion regimen of diazepam commonly used forgastrointestinal endoscopy in Japan. METHODS: Fifteen healthy Japanese volunteers consisting of three different CYP2C19 genotype groups underwent a critical ? icker fusion test, an eye movement analysis and a postural sway test as a test for physical sedative effects, and a visual analog scale (VAS) symptom assessment method as a test for mental sedative effects during the 336 h period after the intravenous infusion of diazepam (5 mg). RESULTS: The physical sedative effects assessed by the critical flicker test continued for 1 h (t values of 5 min, 30 min and 60 min later: 4.35, 5.00 and 3.19, respectively) and those by the moving radial area of a postural sway test continued for 3 h (t values of 5 h, 30 h, 60 min and 3 h later: -4.05, -3.42, -2.17 and -2.58, respectively), which changed significantly compared with the baseline level before infusion (P < 0.05). On the other hand, the mental sedative effects by the VAS method improved within 1 h. The CYP2C19 genotype-dependent differences in the postinfusion sedative effects were not observed in any of the four psychomotor function tests. CONCLUSION: With the psychomotor tests, the objective sedative effects of diazepam continued for 1 h to 3 h irrespective of CYP2C19 genotype status and the subjective sedative symptoms improved within 1 h. Up to 3 h of clinical care appears to be required after the infusion of diazepam, although patients feel subjectively improved.展开更多
To investigate the effect of propofol combined with diazepam on the γ-aminobutyric acid (GABA)-activated chloride current (I GABA ) evoked in rat sensory neurons Methods Whole cell patch clamp recordings were made fr...To investigate the effect of propofol combined with diazepam on the γ-aminobutyric acid (GABA)-activated chloride current (I GABA ) evoked in rat sensory neurons Methods Whole cell patch clamp recordings were made from cultured rat dorsal root ganglionic neurons GABA (3*!μmol/L) was applied by pressure ejection The anesthetics were dissolved in the external solution and given by the “Y-tube" method Results Co-application of propofol (0 3-3*!μmol/L) and diazepam (100*!nmol/L) potentiated the I GABA which was significantly larger than the sum of that potentiated by drug alone Diazepam (100*!nmol/L) shifted the concentration-response curve for the I GABA potentiation induced by propofol to the left in a parallel fashion The EC 50 value for propofol was decreased by diazepam from 7 6±1 8 *!μmol/L to 3 9±1 1*!μmol/L (n=9) Conclusions Our results suggest that propofol combined with diazepam synergistically potentiates the I GABA Diazepam-induced increase in the apparent binding affinity of propofol for the GABA A receptors is likely responsible for a clinical synergistic hypnotic action during co-application with propofol and展开更多
本研究分析了水产养殖和垂钓中饲料、窝料、饵料、水样及水产品中地西泮(Diazepam,DZP)的存在情况,并建立了在线净化-液相色谱串联质谱定量检测方法。结果表明DZP含量在0.5~20.0μg/L间线性良好,相关系数(r^(2))均大于0.999;饵料、水样...本研究分析了水产养殖和垂钓中饲料、窝料、饵料、水样及水产品中地西泮(Diazepam,DZP)的存在情况,并建立了在线净化-液相色谱串联质谱定量检测方法。结果表明DZP含量在0.5~20.0μg/L间线性良好,相关系数(r^(2))均大于0.999;饵料、水样和水产品中定量限(Limit of quantitation,LOQ)分别为1.0μg/kg、0.5μg/L、1.0μg/kg;3种基质中1.0μg/kg、5.0μg/kg和10.0μg/kg 3个浓度水平的加标回收率分别为85.2%~106.5%、82.3%~108.0%、90.7%~116.0%,相对标准偏差(Relative standard deviation,RSD)分别为3.6%~5.1%、2.7%~4.3%、2.1%~2.6%。通过调查发现,7份养殖用饲料中均未检出DZP;28份垂钓中使用的窝料、饵料检出率达66.7%,浓度为2.2~213090.0μg/kg;10份诱鱼剂中均检出DZP,检出率达100%,浓度为637000.0~3471000.0μg/kg;27份水样中DZP检出率达85.2%,浓度为0.4~9.8μg/L和71份淡水鱼中DZP的检出率为54.9%,浓度为0.5~21.8μg/kg。由此可见窝料、饵料及诱鱼剂的使用可能是水体和水产品中DZP频繁检出的重要原因之一,对消费者食用安全和水产养殖行业的健康发展均具有潜在风险,亟需加强DZP监管和监测。展开更多
基金This project was supported by a grant from a nationalnatural sciences foundation of China (No. 30 0 40 0 37)
文摘The protective effect and mechanism of diazepam on ischemia neurons during cerebral ischemia and reperfusion were studied. Sixty three Wistar rats were divided randomly into nine groups: control group , ischemia groups including subgroups of is3h, is3 h/rep1 h, is3 h/rep2 h, is3 h/rep3 h, diazepam treated groups , including subgroups of is3 h, is3 h/rep1 h, is3 h/rep2 h, is3 h/rep3 h with Zea longa’s animal model of middle cerebral artery occlusion. The comparison between the ischemia group and diazepam treated group showed that diazepam could obviously decrease the production of glutamate, asparate, MDA and increase the synthesis and release of GABA, SOD and GSH PX. It was concluded that diazepam exerted its protective effects on neurons through complex mechanisms of regulating the synthesis and release of excitotary/inhibitory amino acids and free radicals.
文摘The solubility enhancement of diazepam and nitrazepam in water was analyzed depending on temperature and amount of α-cyclodextrin ( α-CD), β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The interactions of drug-cyclodextrin in solution were investigated by the phase-solubility analysis. Diazepam (nitrazepam) content in aqueous complexation medium was analyzed UV spectrophotometrically. Classical solubility data were used to derive apparent stability constants (K1:1) which were used to derive thermodynamic parameters for the diazepam (nitrazepam)-cyclodextrin complexes. Since all phase solubility plots were of AL–types, and calculated Slopes after linear regression analysis were found to be less than 1, it could be assumed that stoichiometry of the formed binary systems was 1:1. According to the calculated K1:1 values, the stability of the complexes of diazepam and nitrazepam with a-CD, β-CD and 2-HP-β-CD varies as follows: 2-HP-β-CD > β-CD > β-CD. The a-CD has higher affinity for dissolving nitrazepam compared to diazepam. While all parameters lead to an improvement in solubility, the largest effect was obtained for guest-host complexation with 2-HP-β-CD. The solubility of diazepam and nitrazepam in water increased 93.02 times and 64.23 times, respectively, in the presence of 40% (w/w) 2-HP-β-CD, at 25°C. Solubility data for diazepam and nitrazepam in aqueous 2-HP-b-CD were used to derive thermodynamic parameters, ΔG° at 298 K = –14.43 kJ·mol–1, ΔH° = 0.79 kJ·mol–1, ΔS° at 298 K = 51.17 J·mol–1·K–1 and ΔG° at 298 K = –13.43 kJ·mol–1, ΔH° = 2.38 kJ·mol–1, ΔS° at 298 K = 53.01 J·mol–1·K–1, respectively. Formation of inclusion complexes substantially increases the water solubility of diazepam and nitrazepam. Diazepam and nitrazepam dissolution thermodynamics in aqueous 2-HP-β-CD were characterized by spontaneous and endothermic dissolution and hydrophobic interactions.
基金supported by National Institute of Health(T32GM008424)Whitehall Foundation+1 种基金William C DEGROAT Neuropharmacology Departmental FellowshipPharmacology and Chemical Biology Startup Funds
文摘OBJECTIVE Investigate the effects of diazepam(DZP) on γ2 subunit containing GABA type A receptor(GABA A R) trafficking.METHODS Immunofluorescence microscopy measured surface GABA A Rs and gephyrin in rat cortical neurons after 24 h exposure of 1.0 μmol·L^(-1) DZP.Biochemical studies of mice injected with 10 mg·kg^(-1) DZP vs vehicle were assessed for γ2 subunit and total gephyrin cortical levels 12 h post-injection.Ubiquitination of the γ2 subunit was studied by immunoprecipitation after 12 h of 1.0 μmol·L^(-1) DZP exposure.A γ2 subunit encoding an N terminal fluorogen-activating peptide and pH-sensitive green fluorescent protein(γ2 pH FAP) measured lysosomal targeting of γ2 containing GABA A Rs.RFP-gephyrin and γ2 pH FAP synaptic diffusion rates were examined using fluorescence recovery after photobleaching(FRAP).RESULTS Extrasynaptic levels of γ2 GABA A Rs decreased by 12.2%,while synaptic gephyrin S270 phosphorylation increased by 18.3% in DZP-treated neurons after 24 h compared to control(P<0.05).Dendritic levels of gephyrin were also reduced to 74.1% of control,while S270 phosphorylation was elevated by 25.2%(P<0.05;P<0.01).Mice 12 h post-DZP injection demonstrated a 12.7% and 26.1% decrease in total γ2 and gephyrin levels,respectively(P<0.05;P<0.01).12 h DZP treatment enhanced γ2 subunit ubiquitination 1.13-fold relative to control(P<0.05).Internalized γ2 pH FAP GABA A Rs associated with lysosomes was 8.0% higher in neurons treated with 12-16 h DZP compared to control.Pilot FRAP experiments suggest gephyrin and γ2 have increased mobility and turnover at synapses following DZP.CONCLUSION DZP treatment decreases γ2 GABA A R levels and gephyrin scaffolding function after one day of exposure,which may contribute to the formation of DZP tolerance.
基金Supported by A Grant-in-Aid for Cancer Research from the Ministry of Health,Labor and Welfare of Japan,in part
文摘AIM:To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias.METHODS:Between February 2002 and December 2009,a total of 286 patients with gastric epithelial neoplasia underwent endoscopic submucosal dissection in our hospital.To achieve moderate sedation,5-7.5 mg of diazepam was administered intravenously by non-anesthesiologists.Intermittent additional administration of 2.5-5 mg diazepam was performed if uncontrollable body movement of the patient was observed.All patients were classified into groups based on the required diazepam dose:low-dose (≤ 17.5 mg,n=252) and high-dose (> 17.5 mg,n=79).RESULTS:Differences between the low-and highdose diazepam groups were observed in lifetime alcohol consumption (0.30 ± 0.48 vs 0.44 ± 0.52 tons,P=0.032),body weight (58.4 ± 10.3 vs 62.0 ± 9.9 kg,P=0.006),tumor size (15 ± 10 vs 23 ± 18 mm,P < 0.001),lesion location (P < 0.001) and the presence of ulcerative findings (14/238 vs 18/61,P < 0.001).Multivariate analysis identified all five variables as independently related to required diazepam dosage.In terms of adverse reactions to diazepam administration,paradoxical excitement was significantly more frequent in the high-dose diazepam group (P < 0.001).CONCLUSION:Intermittent administration of diazepam enabled safe completion of gastric endoscopic submucosal dissection except in patients who were alcohol abusers or obese,or who showed complicated lesions.
文摘Recent studies have shown the importance of the GABA-ergic transmission in the pathophysiology of anxiety and depressive disorders in humans. Our present study aims to investigate the interaction of melatonin (MEL) with this system by exploring the effects of MEL with or without a facilitator of GABA-ergic neurotransmission, diazepam (DZ) on the levels of depression and anxiety in Wistar rats. For this purpose, different doses of MEL (2, 4 or 16 mg/kg) or DZ (2 mg/kg) are subchronically administered during 15 days. After pharmacological treatments, anxiety levels are evaluated in behavioral tests of Open Field (OFT) and elevated plus maze (EPM) and depression levels are evaluated by the forced swim test (FST). The results showed that MEL produces anxiolytic-like and antidepressant-like effects in a dose-dependent manner;the maximum effect was obtained at a dose of 16 mg/kg. However, a dose of 4 mg/kg is necessary to induce an effect. The effect of MEL and DZ reported in this study concerns selective modulation of behavioral anxiety and depression since locomotor activity assessed by the OFT and EPM was not affected. The subchronic injection of MEL at 4 mg/kg, DZ at 2 mg/kg or the two combined molecules also induces also anxiety-like and antidepressant-like behavior. In addition, a potentiating effect between MEL and DZ was observed. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to improve the central GABA-ergic transmission.
文摘Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.
文摘The present study analyzed expressional changes of excitatory neurotransmitters and inhibitory neurotransmitters in the rat corpus striatum after single-use and combined-use diazepam and Chinese herb moschus. The influence of moschus on the central nervous system was analyzed, in particular whether moschus increased penetration of other drugs into the brain. Reverse-phase high-performance liquid chromatography, which included pre-column derivation with orthophthaladehyde detection, showed varied increased levels of excitatory neurotransmitters, including aspartate and glutamate, and inhibitory neurotransmitters, including glycine and Y-aminobutyric acid, in the corpus striatum after treatment with moschus alone, diazepam alone, or a combination of both. Compared with the diazepam group, aspartate levels significantly decreased at 30 and 60-105 minutes after combined treatment with moschus, while glutamate significantly increased at 45 and 75-105 minutes, glycine levels significantly increased at 105 minutes, and γ-aminobutyric acid increased at 30 and 75-105 minutes. These findings suggested that moschus increased the inhibition effects of diazepam on the brain.
基金Grants-in-Aid for Scientific Research from YOKOYAMA Foundation for Clinical Pharmacologya Grant-in-Aid from the Center of Excellence (COE) from the Ministry of Education, Culture, Sports, Science and Technology of JapanGrant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan No. 17590470
文摘AIM: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP ) 2C19 genotypes after an infusion regimen of diazepam commonly used forgastrointestinal endoscopy in Japan. METHODS: Fifteen healthy Japanese volunteers consisting of three different CYP2C19 genotype groups underwent a critical ? icker fusion test, an eye movement analysis and a postural sway test as a test for physical sedative effects, and a visual analog scale (VAS) symptom assessment method as a test for mental sedative effects during the 336 h period after the intravenous infusion of diazepam (5 mg). RESULTS: The physical sedative effects assessed by the critical flicker test continued for 1 h (t values of 5 min, 30 min and 60 min later: 4.35, 5.00 and 3.19, respectively) and those by the moving radial area of a postural sway test continued for 3 h (t values of 5 h, 30 h, 60 min and 3 h later: -4.05, -3.42, -2.17 and -2.58, respectively), which changed significantly compared with the baseline level before infusion (P < 0.05). On the other hand, the mental sedative effects by the VAS method improved within 1 h. The CYP2C19 genotype-dependent differences in the postinfusion sedative effects were not observed in any of the four psychomotor function tests. CONCLUSION: With the psychomotor tests, the objective sedative effects of diazepam continued for 1 h to 3 h irrespective of CYP2C19 genotype status and the subjective sedative symptoms improved within 1 h. Up to 3 h of clinical care appears to be required after the infusion of diazepam, although patients feel subjectively improved.
文摘To investigate the effect of propofol combined with diazepam on the γ-aminobutyric acid (GABA)-activated chloride current (I GABA ) evoked in rat sensory neurons Methods Whole cell patch clamp recordings were made from cultured rat dorsal root ganglionic neurons GABA (3*!μmol/L) was applied by pressure ejection The anesthetics were dissolved in the external solution and given by the “Y-tube" method Results Co-application of propofol (0 3-3*!μmol/L) and diazepam (100*!nmol/L) potentiated the I GABA which was significantly larger than the sum of that potentiated by drug alone Diazepam (100*!nmol/L) shifted the concentration-response curve for the I GABA potentiation induced by propofol to the left in a parallel fashion The EC 50 value for propofol was decreased by diazepam from 7 6±1 8 *!μmol/L to 3 9±1 1*!μmol/L (n=9) Conclusions Our results suggest that propofol combined with diazepam synergistically potentiates the I GABA Diazepam-induced increase in the apparent binding affinity of propofol for the GABA A receptors is likely responsible for a clinical synergistic hypnotic action during co-application with propofol and
文摘本研究分析了水产养殖和垂钓中饲料、窝料、饵料、水样及水产品中地西泮(Diazepam,DZP)的存在情况,并建立了在线净化-液相色谱串联质谱定量检测方法。结果表明DZP含量在0.5~20.0μg/L间线性良好,相关系数(r^(2))均大于0.999;饵料、水样和水产品中定量限(Limit of quantitation,LOQ)分别为1.0μg/kg、0.5μg/L、1.0μg/kg;3种基质中1.0μg/kg、5.0μg/kg和10.0μg/kg 3个浓度水平的加标回收率分别为85.2%~106.5%、82.3%~108.0%、90.7%~116.0%,相对标准偏差(Relative standard deviation,RSD)分别为3.6%~5.1%、2.7%~4.3%、2.1%~2.6%。通过调查发现,7份养殖用饲料中均未检出DZP;28份垂钓中使用的窝料、饵料检出率达66.7%,浓度为2.2~213090.0μg/kg;10份诱鱼剂中均检出DZP,检出率达100%,浓度为637000.0~3471000.0μg/kg;27份水样中DZP检出率达85.2%,浓度为0.4~9.8μg/L和71份淡水鱼中DZP的检出率为54.9%,浓度为0.5~21.8μg/kg。由此可见窝料、饵料及诱鱼剂的使用可能是水体和水产品中DZP频繁检出的重要原因之一,对消费者食用安全和水产养殖行业的健康发展均具有潜在风险,亟需加强DZP监管和监测。