Flumazenil, a GABA antagonist, may improve features of Parkinson's disease.

Manipulation of gamma-aminobutyrate (GABA) system has been little studied in Parkinson's disease, despite the fact that GABA subserves a large part of the basal ganglia, including the outflow tracts. To test whether antagonism of GABA could improve features of PD, we administered open label intravenous flumazenil to eight practically defined off patients and assessed UPDRS scores, bilateral 1-minute hand-tapping speed, and timed gait tests. Patients demonstrated significantly greater tapping speed, which peaked 40 minutes after injection (P < 0.05). Total motor Unified Parkinson's Disease Rating Scale scores modestly improved (P < 0.05). There were no adverse events. Mechanisms by which flumazenil could improve PD are discussed.     

Saturation analysis of specific 11C Ro 15-1788 binding to the human neocortex using positron emission tomography

The ¹¹C-labelled benzodiazepine antagonist Ro 15–1788 (flumazenil) and positron emission tomography (PET) were used to determine quantitative characteristics of benzodiazepine receptor binding in the neocortex of healthy young men. Saturating doses of unlabelled flumazenil administered i.v., before or together with the ligand-reduced ¹¹C-flumazenil accumulation in the neocortex by about 90 per cent. Saturating doses of unlabelled flumazenil had little effect on the accumulation of radioactivity in the benzodiazepine receptor-poor regions such as pons or white matter. By giving graded doses of unlabelled flumazenil together with the tracer, saturation isotherms were obtained allowing the calculation of receptor density (B_max) and equilibrium dissociation constant (K_d) values on the basis of certain assumptions B_max values were in the order of 90 pmol/g and K_d values in the order of 10 nM in the neocortex. Scatchard and Hill plots of the radioactivity data indicated that ¹¹C-flumazenil binds to saturable sites of a homogeneous population. The data indicate that intravenous doses of 1 or 2 mg flumazenil result in a benzodiazepine receptor occupancy of about 50 per cent. The method described should be useful for studying regional differences in benzodiazepine receptor characteristics in the living human brain in healthy subjects and neuropsychiatric disorders, and also in relation to treatment with drugs interacting with benzodiazepine receptors.     

国产氟马西尼的临床应用

探讨苯二氮 艹卓 受体拮抗剂 氟马西尼治疗昏迷的临床价值。结果表明 :氟马西尼治疗后 15 ,30 ,6 0和 180minMGCS得分较治疗前依次增加 5 3,8 0 ,9 4和 7 3分 ,较常规药物组分别增加 5 2 ,7 7,8 7和 6 9分 (P <0 .0 1)。治疗后OAA/S得分也较治疗前增加 1 9分 (P <0 .0 1)。治疗过程中除少数患者出现轻度激越现象和窦性心动过速外 ,未发现其它副作用。提示氟马西尼能有效地拮抗因急性苯二氮 艹卓 类药物中毒而引起的意识障碍 ,具有较好的抗昏迷作用     

Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats

The anxiolytic profile of dexmedetomidine, a novel, highly-selective ₂-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1–10 µg/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1–10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 µg/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an ₂-adrenergic antagonist, atipamezole, 10–50 µg/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the ₁-adrenergic antagonist, prazosin, 0.1–10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and ₂-agonist responses do not share any molecular component, there does appear to be crosstalk between these two systems. These may involve GABA or noradrenergic downstream effects of either dexmedetomidine or midazolam, respectively.     

军事人员对抗睡眠剥夺策略的研究进展

现代军事斗争和非军事行动呈现出强度大、突发状况多、连续工作时间长的特点,这势必会造成军事人员的睡眠剥夺。然而高强度的作业需要军事人员随时保持良好的工作能力,突发紧急状况需要军事人员保持良好的警觉状态,长时间的工作更需要军事人员保持良好的精神状态和认知能力。军事人员如何有效地对抗睡眠剥夺,保持警醒状态和极高的应激能力成为现代军事医学研究的热点与重点。本文就中枢兴奋药物、预防性睡眠药物、预防性睡眠后快速复醒药物及非药物方式等对抗睡眠剥夺的研究进展作一综述。     

Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P < 0.05) without altering minute volume (V_E). In combination to DZP, BUP/NLX significantly increased expiratory time (P < 0.01) and decreased f (P < 0.01), tidal volume (V_T, P < 0.001), and V_E (P < 0.001) while BUP only decreased V_T (P < 0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P < 0.001) and decreased f (P < 0.01) and V_E (P < 0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined.     

氟马西尼治疗25例苯二氮(艹卓)类药物中毒的疗效

目的:评价氟马西尼治疗苯二氮类药物(BZDs)中毒患者的疗效和安全性。方法:选择我院急救中心BZDs急性中毒患者50例,随机分为常规治疗组和氟马西尼组各25例,常规治疗为洗胃后给予静脉输入5％葡萄糖溶液,维生素C 6 g·d-1和10％氯化钾3～5 g·d-1静脉滴注,呋塞米利尿、导泻以及抗生素预防性治疗。氟马西尼组在常规治疗基础上用氟马西尼0．25～0．5 mg静注,随后予氟马西尼10μg·min-1静脉泵入,至患者清醒或总量1 mg,如未清醒或再昏迷者继续给予氟马西尼5μg·min-1静脉泵入维持。将两组患者治疗前后昏迷深度评分和机敏力／镇静程度评判量表(OAA／S)得分以及治疗后的平均意识恢复时间和平均住院日进行统计学分析。结果:氟马西尼组昏迷深度评分、OAA／S得分、平均意识恢复时间和平均住院日均小于常规治疗组(P<0．01)。结论:氟马西尼可作为治疗急性BZDs中毒的首选药物之一。     

Modulation of the discriminative stimulus properties of (−)-nicotine by diazepam and ethanol

The effect of different ligands for the GABA-BZD receptor and the NMDA receptor were studied in rats trained to discriminate (?)-nicotine (1.9 μmol/kg) from saline in a standard two-bar operant conditioning paradigm with food reinforcement. MK-801 (0.03–0.3 μmol/kg), flumazenil (10–30 μmol/kg), and Ro 15–4513 (3–10 μmol/kg) did not generalize to (?)-nicotine on nicotine-trained rats, and when tested as antagonists they did not block the nicotine cue. Diazepam (3–10 μmol/kg) and ethanol (11–22 mmol/kg) did not have any effect by themselves, but they significantly attenuated the nicotine cue by 53 and 65%, respectively, without affecting the response rates of the animals. Pre-treatment with flumazenil (30 μmol/kg) reversed the effect of diazepam but it did not reverse the effect of ethanol on the discriminative stimulus properties of (?)-nicotine. The effect of ethanol was not blocked by Ro 15–4513 (10 μmol/kg). These data indicate that diazepam and ethanol modulate the expression of the nicotine cue and that the effect of diazepam is mediated via a benzodiazepine receptor mechanism. © Wiley-Liss, Inc.     

Use of a standardized uptake value for parametric in vivo imaging of benzodiazepine receptor distribution on [<Superscript>11</Superscript>C]flumazenil brain PET

To simplify the acquisition protocol of carbon-11 labeled flumazenil (FMZ) positron emission tomography (PET) for distribution volume (DV) images, we attempted to obtain standardized uptake value (SUV) images compatible with DV images, and assessed the applicability of this method in patients with unilateral cerebrovascular diseases (CVD). [¹¹C]FMZ PET was performed in ten normal subjects. A DV image and ten sequential 5-min SUV images were generated for each subject. We investigated the correlation coefficient (r) and standard estimation of error (SEE) between the latter ten static images and the DV image using the pixel-by-pixel method, thereby determining the optimum acquisition phase. The same FMZ PET procedure was performed in 15 patients with unilateral CVD. Twenty regions of interest (ROIs) were positioned both in lesioned areas and in symmetrical regions. DV and SUV in the optimum phase for each ROI were calculated to compare the lesion-to-normal (L/N) ratio of DV and that of SUV. The highest r and a low SEE (r=0.957, SEE=633) were observed from 30 to 35 min after tracer administration in the study of normal subjects. A high r (0.945) and a low SEE (0.0438) between the DV L/N ratio and the SUV L/N ratio were obtained in the study of patients. Our study suggests that SUV images acquired from 30 to 35 min after FMZ administration are a suitable alternative to DV images not only in normal subjects but also in patients with unilateral CVD. This simple method seems to be valuable for the identification of altered neuronal activity in patients with CVD.