加味酸枣仁合剂治疗广泛性焦虑症对照研究

目的:观察加味酸枣仁合剂治疗广泛性焦虑症的临床疗效和安全性。方法:将195例广泛性焦虑症患者随机分为研究组(加味酸枣仁合剂治疗)98例和对照组(阿普唑仑治疗)97例,疗程6周,于疗前、及治疗后第1、2、4、6周末采用Hamil- ton焦虑量表(HAMA)和副反应量表(TESS)评定疗效和不良反应。结果:两组疗效相似,加味酸枣仁合剂组总有效率为65．3％;阿普唑仑组总有效率69．1％,两组无统计学差异;加味酸枣仁合剂的不良反应以胃肠道症状为主,阿普唑仑的不良反应以嗜睡为主。结论:加味酸枣仁合剂用于治疗广泛性焦虑症安全有效。     

五花舒肝汤治疗失眠52例疗效观察

[目的]观察五花舒肝汤、阿普唑仑治疗失眠的临床疗效和不良反应.[方法]将102例失眠患者随机分为二组,中药治疗者组用五花舒肝汤加减治疗,西药对照组用阿普唑仑治疗,4周为1疗程,观察二组患者失眠缓解情况、不良反应发生情况.[结果]中药治疗组治愈10例,显效14例,有效19例,无效9例;西药对照组治愈11例,显效16例,有效17例,无效6例;治疗组与对照组之间治愈率、显效率、总有效率均无明显差异(P＞0.05);不良反应中药治疗组9例,西药对照组19例,两组有明显差异(P＜0.05).[结论]中药治疗可以有效缓解失眠,与苯二氮卓类药物阿普唑仑疗效相当;但中药不良反应更少,易于被患者接受.     

A double-blind,placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers

Rationale Pregabalin potently and selectively binds to the alpha₂-delta subunit of voltage-dependent calcium channels, reducing calcium influx and modulating release of downstream excitatory neurotransmitters, such as glutamate. Pregabalin has demonstrated robust efficacy for several disease states, but its neuropharmacology is still being elucidated.Objective This study was conducted to evaluate the cognitive and psychomotor effects of oral pregabalin (150 mg t.i.d.) using alprazolam (1 mg t.i.d.) as a positive internal control and placebo.Methods Twenty-four healthy volunteers were randomised to a double-blind, three-way crossover study. Each period consisted of 3-day double-blind treatment followed by 1 day of single-blind placebo. Psychometrics included tests of Choice Reaction Time (CRT), CNS arousal (Critical Flicker Fusion, CFF), vigilance (Rapid Visual Information Processing, RVIP), serial memory scanning (Sternberg Short-Term Memory Scanning Test, STM), divided attention (Compensatory Tracking Task, CTT), Brake Reaction Time (BRT) in an on-the-road vehicle, and subjective Line Analogue Rating Scales (LARS) for sedation.Results Pregabalin showed no significant effects on the objective psychometrics—CRT, BRT, RVIP, STM—compared with placebo. Pregabalin produced a limited, significant decrement on CFF and CTT and a significant effect on the LARS. Pregabalin was associated with improvement relative to placebo in BRT. The positive control, alprazolam, produced significant impairment on all objective measures and significant impairment on the LARS, thus establishing the sensitivity of the test battery used in the study.Conclusions Pregabalin did not differ on most assessments from placebo, producing only minor, transient impairment on some objective cognitive and psychomotor measures, suggesting a relatively benign CNS side-effect profile.     

The staircase test: Some evidence of nonspecificity for anxiolytics

In the staircase test, a naive mouse is placed in a Plexiglas chamber containing a five-step staircase, and the number of rearings and steps climbed are recorded for 3 min. A claim for drug-class specificity has been made because conventional anxiolytics reduced rearings at doses that did not reduce steps climbed, while non-anxiolytics affected both measures in parallel. In the present study chlordiazepoxide, meprobamate, and ethanol registered the expected true positive effect by reducing rearings at doses that did not reduce steps climbed. Nicotine, which has some clinical anxiolytic action, registered a small true positive. The benzodiazepine anxiolytic alprazolam reduced both measures, a false negative, although it reduced rearings more than steps climbed. The putative novel anxiolytics CGS 9896, ketanserine, and tracazolate registered negatives, as did the known clinical anxiolytic buspirone. The non-anxiolytics phencyclidine and phenacetin registered true negatives, but morphine registered a clear false positive. The anxiogenics FG 7142 and pentylenetetrazol produced no significant effects. Because of the equivocal false negative for alprazolam, the clear false negative for buspir-one, and the clear false positive for morphine, we concluded that the test lacks the degree of therapeutic-class specificity previously proposed but may still be useful in basic research.     

帕罗西汀联合阿普唑仑治疗广泛性焦虑症的疗效观察

目的探讨帕罗西汀联合阿普唑仑治疗广泛性焦虑症患者的疗效,关注其对焦虑和抑郁评分的影响,以期为临床工作提供帮助。方法收集本院诊治的广泛性焦虑症的患者80例,随机分为观察组（40例）与对照组（40例）,对照组单纯应用帕罗西汀治疗,观察组应用帕罗西汀联合阿普唑仑治疗,观察治疗对患者焦虑和抑郁评分的影响。结果观察组在治疗2、4、8周后对焦虑和抑郁的改善情况明显优于对照组,两组差异有统计学意义（P〈0.05）。结论帕罗西汀联合阿普唑仑治疗广泛性焦虑症患者的疗效明显,对焦虑和抑郁改善的效果理想,临床中可以积极应用。     

Caffeine augments Alprazolam induced cytotoxicity in human cell lines

Combined effects of alprazolam (Alp), a member of benzodiazepine group of drugs and caffeine on human cell lines, HeLa and THP1 were investigated in this study. Alp mediated cytotoxicity was enhanced while caffeine was present. The cell death was confirmed by observing morphological changes, LDH assay and membrane anisotropic study. Also such combined effects induced elevated level of ROS and depletion of GSH. The mechanism of cell death induced by simultaneous treatment of Alp and caffeine was associated with the calcium-mediated activation of μ-calpain, release of lysosomal protease cathepsin B, activation of PARP and cleavage of caspase 3. Our results indicate that, Alp alone induces apoptosis in human cells but in the presence of caffeine it augments necrosis in a well-regulated pathway. Thus our observations strongly suggest that, alprazolam and caffeine together produce severe cytotoxicity in human cell lines.     

Inhibition of CYP3A4 and CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as racemate and four different enantiomers

Objective The antifungal drug ketoconazole (KTZ) is known as an inhibitor of, especially, the CYP3A subfamily, which catalyzes the metabolism of a large variety of drugs. Interactions between KTZ and CYP3A substrates have been reported both in vivo and in vitro. Most of them, however, involved the KTZ racemate. KTZ racemate and the separate enantiomers, 2R,4R; 2R,4S; 2S,4S, and 2S,4R, were evaluated for their selectivity in inhibiting alprazolam and quinine metabolism. Methods The inhibition of alprazolam and quinine metabolism was studied in an in vitro system of human liver microsomes (HLM), recombinant of CYP3A4 and CYP3A5. The concentrations of formed 3-hydroxyquinine and 4- and α-hydroxyalprazolam were measured by HPLC and LC-MS, respectively. Results Quinine 3-hydroxylation was catalyzed to a similar extent by CYP3A4 and CYP3A5. The formation rate of 4-hydroxyalprazolam was higher than that of α-hydroxyalprazolam for each HLM, CYP3A4 and CYP3A5. KTZ racemate and enantiomers showed differential inhibitory effects of quinine and alprazolam metabolism. Quinine metabolism catalyzed by HLM, CYP3A4 and CYP3A5 was potently inhibited by the trans-enantiomer KTZ 2S,4S, with IC₅₀ value of 0.16 μM for HLM, 0.04 μM for CYP3A4 and 0.11 μM for CYP3A5. The same enantiomer showed the lowest IC₅₀ values of 0.11 μM for HLM and 0.04 μM for CYP3A5 with respect to alprazoalm 4-hydroxylation and also the same pattern for alprazolamα-hydroxylation, 0.13 μM for HLM and 0.05 μM for CYP3A5. Alprazolam metabolism (both α- and 4- hydroxylations) catalyzed by CYP3A4 was inhibited potently by the cis-enantiomer KTZ 2S,4R, with IC₅₀ values of 0.03 μM . Conclusions Alprazolam and quinine metabolism is catalyzed by both CYP3A4 and CYP3A5. The present study showed that different KTZ enantiomers inhibit CYP3A4 and CYP3A5 to different degrees, indicating that structural differences among the enantiomers would be related to their inhibitory potency on these two enzymes.     

低剂量奥氮平治疗老年慢性失眠症的临床观察

目的:探讨对老年慢性失眠症的有效治疗方法.方法:用随机对照方法,将120例老年慢性失眠症患者按随机数字表法分为奥氮平组和阿普唑仑组,治疗4周.采用匹兹堡睡眠质量指数(pittsburgh sleep quality index,PSQI)及药物不良反应量表评定临床疗效和不良反应.结果:奥氮平组在治疗第四周时PSQI总分、汉密顿焦虑量表(Hamilton anxiety scale,HAMA)、汉密顿抑郁量表(Hamilton depression raling scale,HAMD)、临床显效率分别为(5.2±1.8)分、(11.5±5.4)分、(5.1±2.3)分、91.7％,明显优于阿普唑仑组(6.8±2.5)分、(17.5±7.8)分、(9.9±5.8)分、68.3％,差异具有显著性(P＜0.05).结论:低剂量奥氮平不仅能显著改善慢性失眠症患者的睡眠状况,而且可以明显减少患者日常功能的缺失.     

帕罗西汀治疗老年原发性失眠症的对照研究

目的探讨帕罗西汀治疗老年原发性失眠症的疗效和副作用。方法采用随机单盲安慰剂对照方法将90例老年原发性失眠症患者随机分为帕罗西汀组(30例)、阿普唑仑组(30例)和安慰剂组(30例),对照治疗12周。采用匹兹堡睡眠质量指数、临床疗效和治疗药物副作用量表评定疗效和副作用。结果帕罗西汀组显效率83%,阿普唑仑组53%。经χ2检验,P<0.01。帕罗西汀组常见副作用有口干、便秘、恶心等,但较阿普唑仑组为轻微。结论帕罗西汀治疗老年原发性失眠症疗效确切,副作用轻微。     

Independent interaction of alprazolam and caffeine under chronic dose regimens on differential reinforcement of low-rate (DRL 45-s) performance

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7–12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.