Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil.
ABSTRACT The effects of flumazenil, a benzodiazepine receptor antagonist, on triazolam- and zolpidem-induced memory impairment were investigated. Sixty subjects received oral triazolam 0.5 mg, zolpidem 20.0 mg, or placebo at 10 a.m. (n = 20 per drug). Ninety minutes later, half of the subjects (n = 10) in each oral drug group were administered flumazenil 1.0 mg, while the remaining half received placebo (normal saline), through indwelling venous catheters. Learning/memory tests (including Simulated Escape, Restricted Reminding, Paired-Associates, and Repeated Acquisition) were administered at that time, and at 1.5-h intervals over the next 6 h. Triazolam/placebo and zolpidem/placebo drug combinations impaired memory on all tests (all Ps < 0.05). However, the triazolam/flumazenil and zolpidem/flumazenil groups showed no evidence of impairment during any test session. These results demonstrate that flumazenil 1.0 mg rapidly and lastingly reverses memory impairment caused by agonists of the benzodiazepine receptor. Furthermore, nonsignificant trends suggested that performance of the placebo/flumazenil group was consistently better than that of the placebo/placebo group, denoting a possible role of endogenous benzodiazepine agonists in natural sleep/wake processes.
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ABSTRACT: Benzodiazepines are well known for their therapeutic properties, which include anxiolytic, anticonvulsant, muscle-relaxant, and hypnotic effects. Central-type benzodiazepine receptors (CBRs), which are considered to mediate these effects, are present exclusively in the central nervous system (CNS), where they are located on the outer cell membranes of neurons. Peripheral-type benzodiazepine receptors (PBRs) are present in peripheral tissues and also in glia cells of the CNS. Although CBRs are located primarily on the cell membranes of neurons, PBRs are particularly abundant on the membranes of mitochondria. CBR are coupled to γ-aminobutyric acid A (GABAA) receptors, but PBRs are not. PBRs are constituted of at least three protein subunits of different molecular weights, i.e., 18-kDa, 32-kDa, and 30-kDa protein subunits. PBRs have been implicated in various functions, including steroidogenesis, mitochondrial respiration, cell growth and differentiation, and responses to stress. The presence of PBRs in glia of the CNS suggests that they may be involved in glial functions in the brain. This review discusses the involvement of glial PBRs in various neurological diseases, such as degenerative brain diseases, neurotoxic insults, brain damage, brain cancer, and anxiety disorders. It is suggested that the involvement of PBRs in steroidogenesis appears to play an important role in neuroprotection. It is also suggested that PBRs may play a role in glial uptake of excitatory amino acids and their clearance from the brain, and herewith execute neuroprotective capabilities. With this review, we hope to clarify the potential of PBRs as targets for treatment of neurological disorders and prevention of brain damage. Drug Dev. Res. 50:355–370, 2000. © 2000 Wiley-Liss, Inc.Drug Development Research 07/2000; 50(3-4):355-370. DOI:10.1002/1098-2299(200007/08)50:3/43.0.CO;2-W · 0.73 Impact Factor
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ABSTRACT: A rapid and high sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed and validated for the quantification of zolpidem in human EDTA plasma using ondansetron (IS) as an internal standard. The analyte and IS were extracted from human plasma using ethyl acetate and separated on a C18 column (Inertsil-ODS, 5 µm, 4.6 × 50 mm) interfaced with a triple quadrupole tandem mass spectrometer. The mobile phase, which consisted of a mixture of methanol and 20 mM ammonium formate (pH 5.00 ± 0.05; 75:25 v/v), was injected at a flow rate of 0.40 mL/min. The retention times of zolpidem and IS were approximately 1.76 and 1.22. The LC run time was 3 min. The electrospray ionization source was operated in positive ion mode. Multiple reaction monitoring used the [M + H](+) ions m/z 308.13 → 235.21 for zolpidem and m/z 294.02 → 170.09 for the ondansetron, respectively. Five freeze-thaw cycles was established at -20 and -70°C.The linearity of the response/concentration curve was established in human EDTA plasma over the concentration range 0.10-149.83 ng/mL. The lower detection limit [(signal-to-noise (S/N) > 3] was 0.04 ng/mL and the lower limit of quantification (S/N > 10) was 0.10 ng/mL. This LC-MS-MS method was validated with intra-batch and inter-batch precision of 0.52-8.66.The intra-batch and inter-batch accuracy was 96.66-106.11. Recovery of zolpidem in human plasma was 87.00% and IS recovery was 81.60%. The primary pharmacokinetic parameters were T(max) (h) = (1.25 ± 0.725), C(max) (ng/mL) (127.80 ± 34.081), AUC(0→t), = (665.37 ± 320.982) and AUC(0→∞), 686.03 ± 342.952, respectively.Journal of chromatographic science 07/2012; 50(6):538-46. DOI:10.1093/chromsci/bms070 · 1.03 Impact Factor