Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease

1. Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.

2. Here, our aim was to study the interaction between BChE and fluoxetine.

3. Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the V_m, K_m, k_cat and k_cat/K_m values were found to be 20.59?±?0.36?U mg^?1 protein, 194?±?14?µM, 1.3?×?10⁸?s^?1 and 6.7?×?10⁵?µM^?1s^?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC₅₀ value of 104?µM and a K_i value of 36.3?±?4.7?µM.

4. Overall, both the low K_i value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

     

脑梗死后抑郁与负性生活事件相关性研究

目的　探讨脑梗死后抑郁与负性生活事件的关系。方法　将脑梗死患者按是否受负性生活事件影响分为 A(n=75 )、B(n=73)两组。采用抑郁自评量表 (SDS)及 Hamilton抑郁量表筛查 ,对两组进行比较分析 ,并观察其治疗效果。结果　A、B两组脑梗死后抑郁的发生率分别为 5 6 %、38.4 % ,两者比较差异显著 (P<0 .0 5 ) ;百忧解可显著改善或治愈脑梗死后抑郁 ,总有效率 6 1.7%。结论　脑梗死后抑郁发生与负性生活事件相关。百忧解治疗有效     

氟西汀对2型糖尿病合并抑郁症患者下丘脑-垂体肾上腺轴功能及临床疗效的影响

目的探讨氟西汀对 2型糖尿病合并抑郁症患者的下丘脑 垂体 肾上腺轴 (HPA)功能的影响及其临床意义。方法测定 98例 2型糖尿病患者和 3 4例正常对照组基础血皮质醇 (F ,0 8:0 0am、16:0 0pm)、小剂量地塞米松抑制试验 (DST)后血F、2 4h尿游离皮质醇 (UFC)。将 64例 2型糖尿病伴发抑郁症患者随机分成A组 (服用氟西汀组 ,3 2例 )和B组 (未服用氟西汀组 ,3 2例 )。予 6周治疗。分别于治疗前、后进行HAMD评分及代谢控制水平评估。结果 ( 1)血F( 0 8:0 0am、16:0 0pm)、2 4h尿UFC、DST脱抑制例数2型糖尿病患者较正常对照组增高 (P <0 .0 1) ,2型糖尿病伴抑郁症组 (DD组 )较无抑郁症组 (DM组 )增高(P <0 .0 5 ,P <0 .0 1)。 ( 2 )经 6周治疗后 ,服用氟西汀组 (A组 )较未服用氟西汀组 (B组 )糖皮质激素水平降低 (P <0 .0 1)、HAMD评分降低 (P <0 .0 1) ,糖脂代谢改善 (P <0 .0 5 ,P <0 .0 1)。 ( 3 ) 2 4h尿UFC与HbA1C呈正相关性 (r =0 .5 69,P <0 .0 1)、IR呈正相关 (r =0 .65 3 ,P <0 .0 1)、与HAMD评分呈正相关性 (r =0 .3 5 2 ,P <0 .0 5 )。结论 2型糖尿病及合并抑郁症患者HPA轴功能紊乱 ,加重了糖代谢紊乱和胰岛素抵抗 ;氟西汀干预治疗抑郁症可改善抑郁症和糖脂代谢。     

单用氟西汀与联合理性情绪疗法治疗抑郁症对照

目的观察理性情绪疗法在抑郁症治疗中的效果。方法将69例抑郁症患者随机分为两组，A组34例单用氟西汀治疗，B组35例采用理性情绪疗法合并氟西汀治疗。疾病严重程度及疗效采用汉密顿抑郁量表和抑郁自评量表评定，进行了为期12周的观察。结果A、B两组疗效在4周前无显著性差异，但在4～6周开始显示出差异（P〈0．05），8～12周有非常显著性差异（P〈0.01）。B组疗效明显优于A组。结论氟西汀联合理性情绪疗法对抑郁症的疗效比单纯氟西汀治疗更有效。     

Cocaine decreases self-control in rats: a preliminary report

Cocaine abuse is often associated with behavior that takes into account short-term, but not long-term consequences. However, there has been no empirical research concerning the effects of cocaine on self-control (choice of a larger, more delayed reinforcer over a smaller, less delayed reinforcer). In the present research, when food-deprived rats repeatedly chose between a larger, more delayed food reinforcer and a smaller, less delayed food reinforcer, chronic intraperitoneal injections of 15 mg/kg cocaine (but not 10 mg/kg fluoxetine) decreased the rats' choices of the larger, more delayed reinforcer. Cocaine can decrease rats' self-control.     

Prolonged but not acute fluoxetine administration produces its inhibitory effect on hippocampal seizures in rats

This study assessed the effects of acute as well as long-term administration of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor with anti-depressant properties, on hippocampal (HIP) seizures elicited by electrical stimulation in rats. The fluoxetine effect on HIP seizures was also assessed following long-term treatment with gepirone, a 5-HT_1A receptor agonist. Acute single administration of fluoxetine (1, 10 mg/kg; IP) was found to produce no significant effect on HIP seizure activity. Following daily IP administration of fluoxetine (10 mg/kg per day) or gepirone (10 mg/kg per day) for 21 days, animals were given a 7-day drug-free period and then challenged with an acute dose of 10 mg/kg fluoxetine. These treatment regimens resulted in a significantly increased afterdischarge threshold of HIP seizures in response to acute fluoxetine administration. The inhibitory effect of fluoxetine, however, was not present 4 weeks after long-term treatment with either fluoxetine or gepirone. The present results indicate that long-term treatment with these compounds enhances the antiepileptic effect of subsequent fluoxetine administration on the generation of HIP seizures. This effect is possibly related to the well-demonstrated evidence that fluoxetine and gepirone, on long-term treatment, facilitate net 5-HT neurotransmission through desensitization of presynaptic 5-HT autoreceptors.     

氟西汀治疗高血压伴抑郁症状的疗效分析

目的 评价氟西汀治疗高血压伴抑郁症状的效果。方法 70例原发高血压病伴抑郁症状的患者，分成治疗组和对照组，两组均用降压药物治疗，治疗组加用氟西汀，两周后观察疗效。结果 治疗组和对照组的有效率分别为78．9％和56．3％。两组比较差异显著。结论 氟西汀治疗高血压伴抑郁症状有显著疗效。     

Moclobemide versus fluoxetine for a major depressive episode

The efficacy and tolerability of moclobemide (300–600 mg daily) and fluoxetine (20–40 mg daily) were compared in a 6-week, double-blind study of 65 inpatients and 34 outpatients suffering from major depressive episodes (DSM III-R). No statistically significant differences between the two treatment groups were noted regarding efficacy (HDRS, CGI) or safety (adverse events, laboratory examination, vital signs). Moclobemide (300–600 mg daily) and fluoxetine (20–40 mg daily) would thus appear to be comparable both in antidepressant efficacy and tolerability. Doubling the low dosage in non-responders after 3 weeks resulted in a statistically significant improvement of CGI in the moclobemide group by comparison with the fluoxetine group at study end, suggesting that 600 mg moclobemide/day can still improve the patient's condition, while 40 mg fluoxetine/day does not. Sexual dysfunction was reported in two patients taking fluoxetine.     

A Study of Fluoxetine in Obese Elderly Patients with Type 2 Diabetes

In order to establish the safety and efficacy of fluoxetine in subjects over 60 years of age with Type 2 diabetes, a randomized, double-blind, parallel study of 30 obese subjects was undertaken, comparing the use of fluoxetine 60 mg daily with placebo. Subjects were diet controlled with an HbA₁ < 14% (reference range 6–9%) and BMI > 29 kg m². Those taking fluoxetine had a median weight loss of 2.6 kg at 3 months (p < 0.001) and 3.9 kg at 6 months (p < 0–02), compared with weight loss in the placebo group of 0.1 kg and 0.0 kg at 3 and 6 months, respectively. Improved glycaemic control was also demonstrated in the fluoxetine group compared with placebo, initial HbA₁ levels of 8.0% vs 8.7% (NS) falling at 4 months by 0.9% (p < 0.02) and at six months by 0.9% (p < 0.02). No sustained improvement in fasting blood glucose levels was demonstrated. Reporting of adverse events was similar in both groups. Fluoxetine in the short term aids weight loss and improves glycaemic control without a significant increase in adverse events in elderly Type 2 diabetic subjects.     

米氮平与氟西丁治疗老年抑郁症患者的对照研究

目的探讨米氮平治疗老年抑郁症患者的疗效和副反应。方法46例符合CCMD-3抑郁症诊断标准的年龄〉60岁老年抑郁症患者，应用米氮平和氟西丁各23例进行随机对照研究，观察6周，采用汉密顿抑郁量表（HAMD）和副反应量表（TESS）观察患者对治疗的疗效和副反应的变化。结果两种药物疗效相仿，米氮平起效快，副反应少。结论米氮平治疗老年抑郁症患者安全有效，副反应小。