Study pharmacologic of the GABAergic and glutamatergic drugs on seizures and status epilepticus induced by pilocarpine in adult Wistar rats

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.     

Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals.The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis.We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT_1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.     

Rapid antidepressant effect of S-ketamine in schizophrenia

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.     

Regulation of cytochrome P450 gene expression by ketamine: a review

Introduction: Although used as an anesthetic drug for decades, ketamine appears to have garnered renewed interest due to its potential therapeutic uses in pain therapy, neurology, and psychiatry. Ketamine undergoes extensive oxidative metabolism by cytochrome P450 (CYP) enzymes. Considerable efforts have been expended to elucidate the ketamine-induced regulation of CYP gene expression. The safety profile of chronic ketamine administration is still unclear. Understanding how ketamine regulates CYP gene expression is clinically meaningful.

Areas covered: In this article, the authors provide a brief review of clinical applications of ketamine and its metabolism by CYP enzymes. We discuss the effects of ketamine on the regulation of CYP gene expression, exploring aspects of cytoskeletal remodeling, mitochondrial functions, and calcium homeostasis.

Expert opinion: Ketamine may inhibit CYP gene expression through inhibiting calcium signaling, decreasing ATP levels, producing excessive reactive oxygen species, and subsequently perturbing cytoskeletal dynamics. Further research is still needed to avoid possible ketamine–drug interactions during long-term use in the clinic.     

Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies

Suicide is the 14^th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.     

听觉诱发电位指数对无痛人流术麻醉深度的调控

目的评价异丙酚和异丙酚复合氯胺酮用于无痛人工流产的临床效果。方法50例早期妊娠分成异丙酚组（Ⅰ组）和异丙酚复合氯胺酮组（Ⅱ组）各25例，观察两组用药总量、手术各时点听觉诱发电位指数（AAI）、呼吸循环参数改变。采用A—LINE无创麻醉深度监测仪监测AAI值。结果Ⅰ组异丙酚用量明显多于Ⅱ组；两组AAI值在给药后及整个手术期间均明显降低（P〈0．01），Ⅱ组AAI下降的时间及恢复时间滞后于Ⅰ组，Ⅰ组在术后7分钟、Ⅱ组在术后10分钟升至给药前水平；给药后两组平均动脉压（MAP）均有下降（P〈0．05）；Ⅱ组与Ⅰ组相比，SpO2在给药后、手术开始时、手术1分钟及术后1、4分钟时差异有显著性意义（P〈0．05）；Ⅰ组在给药后、手术前4分钟与术后前4分钟SpO2降低（P〈0．05），Ⅱ组SpO2在给药后各时点无明显变化；Ⅰ组术中体动6例，Ⅱ组中无体动。结论AAI的监测更能保证手术的顺利进行和患者的安全。     

靶控输注丙泊酚-氯胺酮静脉麻醉在剖宫产手术中的临床观察

目的：探讨靶控输注丙泊酚-氯胺酮静脉麻醉在剖宫产手术中的临床效果。方法172例择期剖宫产术的产妇,分为观察组86例和对照组86例。观察组采用静脉复合麻醉,麻醉药为丙泊酚、氯胺酮,进行靶控输注。对照组采用脊麻。对观察组和对照组胎儿娩出前和胎儿娩出后产妇的血氧饱和度（SpO2）、心率（HR）、收缩压（SBP）和舒张压（DBP）进行监测,新生儿1 min、5 min和10 min时的Apgar评分进行记录。结果观察组和对照组在胎儿娩出前、后SpO2、HR、SBP、DBP比较差异无统计学意义（P＞0.05）,新生儿1 min、5 min和10 min时的Apgar评分比较差异无统计学意义（P＞0.05）。结论在剖宫产手术中应用靶控输注丙泊酚-氯胺酮静脉麻醉是可行的。     

Use of naltrexone in ketamine dependence

Ketamine is used as a cheap alternative to anaesthetic agents in developing countries. It is also misused as a rave drug because of its psychedelic effect. There are no guidelines for effective management of ketamine withdrawal effects or dependence. Herein we report a case of ketamine dependence and its successful treatment with opioid receptor antagonist naltrexone.     

七氟烷、氯胺酮静吸复合用于小儿腹股沟斜疝修补术的效果及不良反应分析

目的分析和探讨七氟烷、氯胺酮静吸复合用于小儿腹股沟斜疝修补术的临床效果及不良反应情况。方法将我院2012年12月至2014年3月收治的90例行腹股沟斜疝修补术的患儿随机分为观察组和对照组,每组45例。观察组给予七氟烷、氯胺酮静吸麻醉,对照组采用七氟烷进行麻醉,对两组患儿的麻醉效果及不良反应情况进行比较和分析。结果对照组患儿的苏醒时间和清醒时间均显著短于观察组,差异具有统计学意义(P<0.05),观察组出现12例不良反应,占20.00%,对照组出现27例不良反应,占60.00%,两组患儿不良反应的比较差异显著(P<0.05)。结论七氟烷、氯胺酮精细符合用于小儿腹股沟斜疝修补术麻醉效果显著,复合麻醉有效降低了患儿不良反应的发生,值得临床推广使用。     

东莨菪碱对氯胺酮依赖者焦虑障碍治疗的临床疗效观察

目的：观察东莨菪碱对氯胺酮依赖者焦虑障碍的治疗效果。方法：对30例氯胺酮依赖者焦虑障碍给予东莨菪碱治疗,采用 HAMA 量表评价出院时,出院1、3月后的治疗效果。结果：治疗后患者焦虑症状消失,情绪明显改善,对氯胺酮的渴求明显减弱或消失。结论：东莨菪碱治疗氯胺酮依赖者焦虑障碍具有一定的疗效。