Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(–)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid E_max pharmacodynamic model, yielding estimates of both maximal effect (E_max) and sensitivity (IC₅₀) to the racemic and enantiomeric forms of ketamine. R(–)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (E_max)for R(–)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC₅₀) was 1.8±0.5g/mL for R(–)-ketamine; 2.0±0.5 g/mL for R,S(±)-ketamine; and 0.8±0.4 g/mL for S(+)-ketamine. Because the maximal effect (E_max) of the R(–)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC₅₀) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.This work was supported in part by a Starter Grant from the American Society of Anesthesiologists, the Biomedical Research Support Grant NIH 2S07RR5353-20, 1981, (P.F.W.); and NIH and NIA Research Grants NS-17956 and AG03104 (D.R.S., A.J.T., L.B.S). The research fellowship of Dr. Schüttler was made possible by a NATO Foundation Grant (300-402-511-3), awarded by the German Academic Exchange Service. This study is part of Dr. Schüttler's Habilitation Thesis for the Faculty of Medicine at the University of Bonn, West Germany. Dr. Verotta is a fellow of the program of advanced training established by EEC and Regione Lombardia on leave of absence from Mario Negri Institute of Pharmacological Research, Milan, Italy.     

生物样品中氯胺酮的提取与检测方法技术新进展

目的综述各种生物检材中提取检测氯胺酮及其代谢物的方法。方法参考国内外相关文献,介绍了各生物检材特点,并列举了多种预处理和分析方法的优势与不足。结果由于氯胺酮的特殊药理作用,其娱乐性滥用现象较为严重和普遍,因此被列入新型毒品范畴。本文综述了几种快速、准确地检测出人体内氯胺酮及其代谢物的方法,并对各方法特点进行了总结概括。结论氯胺酮生物检材的提取检测方法正沿着更加方便、快速、准确的方向发展。     

低剂量氯胺酮对MPTP诱导帕金森病小鼠神经功能及炎性因子的影响#br# #br#

摘要：目的　探讨低剂量氯胺酮对MPTP诱导帕金森病（PD）小鼠神经功能及神经炎症的影响。方法　50只C57BL/6小鼠按照随机数字表法分为NC组、PD组、PD+Keta-L组、PD+Keta-M组和PD+Keta-H组,每组10只。PD+Keta-L、PD+Keta-M、PD+Keta-H组分别用25、50和75 mg/kg的氯胺酮腹腔注射处理,每天1次,共2 d,而后PD组及PD+Keta-L、PD+Keta-M、PD+Keta-H组腹腔注射MPTP 20 mg/kg,每天1次,连续20 d,建立亚急性PD小鼠模型。观察各组小鼠步态、改良神经功能缺损评分（MNSS）;HE染色观察脑部神经细胞形态变化;免疫组化法检测神经细胞酪氨酸羟化酶（TH）表达,原位缺口末端标记（TUNEL）法检测神经细胞凋亡情况;酶联免疫吸附测定（ELISA）法检测脑组织肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、IL-1β水平;Western blot法检测脑组织Toll样受体4（TLR4）、髓样分化因子88（MyD88）、核因子（NF）-κB p65蛋白水平。结果　与NC组相比,PD组步态异常,MNSS评分、脑组织神经细胞凋亡率以及TNF-α、IL-6、IL-1β水平升高,TH阳性细胞比例降低（P＜0.05）;与PD组相比,PD+Keta-L组步态改善,MNSS评分、神经细胞凋亡率、TNF-α、IL-6、IL-1β水平降低,TH阳性细胞比例升高（P＜0.05）,PD+Keta-M、PD+Keta-L组与PD组比较差异无统计学意义。PD组中TLR4、NF-κB p65和MyD88表达显著高于NC组,与PD组相比,PD+Keta-L组TLR4、NF-κB p65和MyD88均显著降低,PD+Keta-M组仅TLR4及MyD88降低（均P＜0.05）,而PD+Keta-H组无明显变化（P＞0.05）。结论　低剂量氯胺酮对PD小鼠具有一定神经保护作用。     

Presence of the ketamine analog of 2-fluorodeschloroketamine residues in wastewater

Ketamine (KET) analogs are increasingly emerging as new psychoactive substances (NPS). The present report describes the first detection of the KET analog, 2-fluorodeschloroketamine (2F-DCK), in influent samples collected from nine wastewater treatment plants in seven major Chinese cities from 2018 to 2020 by wastewater-based epidemiology (WBE). An analytical method based on solid-phase extraction and subsequent gas chromatography–mass spectrometry was developed for the detection of 2F-DCK and KET. The stability experiments showed that 2F-DCK and KET remained stable in wastewater for 15 days at room and frozen temperatures, and at two pH values (pH = 7 and pH = 2), with residue amounts between 90% and 110%. KET was detected in all samples, whereas 2F-DCK was detected in only four samples: from Guangzhou in 2018, Shenzhen in 2019, and Quanzhou and Nanning in 2020, indicating that 2F-DCK has been used as early as 2018 in China. The renal clearance of 2F-DCK was predicted based on the quantitative structure–pharmacokinetic relationship model, which was used to calculate an excretion factor of 3.7. The 2F-DCK consumption in four cities ranged from 3.71 ± 0.05 to 55 ± 0.09 mg/day/1000 inh, and KET ranged from 1.3 ± 0.04 to 76.5 ± 4.63 mg/day/1000 inh. This is the first study to investigate 2F-DCK by WBE, which provides relevant real-time data on the growth of NPS use, as well as useful information for the government to develop new policies.     

The Rise of Club Drugs in a Heroin Society: The Case of Hong Kong

Although the contemporary dance drug scene is a global phenomenon, with many countries and cultures reporting similar developments with ecstasy and other club drug use, the scene, in many respects, is a reflection and expression of local culture. This article examines the rise of the dance drug scene in a society long associated with opiate use. After briefly describing Hong Kong's drug history, this article describes the diversification of its drug market to include ecstasy and ketamine in the context of a distinctive dance setting. The paper examines the trends in club drug use, particularly with the emergence of the dance scene, motivations to use, types of users, and the problems they experience with club drugs. The paper discusses the reasons for the rise and popularity of club drugs in the context of other locally available drugs, in particular, heroin. This discussion draws from three studies that tracked drug use trends from 1995 to 2002 through a variety of data sources, including official statistics, field observations, individual interviews with 20 law enforcement officials, 16 focus groups with outreach and drug treatment workers, teachers, and representatives from different communities, and in-depth interviews with 27 club drug users.     

Profiles of Club Drug Users in Treatment

There is little in the literature about treatment of persons with problems with “club” or “party” drugs. This paper looks at the characteristics of individuals admitted to treatment for primary, secondary, or tertiary problems with club drugs such as ecstasy, gamma-hydroxybutyrate (GHB), ketamine, flunitrazepam (Rohypnol), methamphetamine, and hallucinogens (e.g., LSD) in programs funded by the Texas Commission on Alcohol and Drug Abuse. Some 38,350 unduplicated records from 1988 through 2003 of persons admitted with problems with club drugs were compared against users of alcohol or other drugs. Club drug users were more impaired on five of six Addiction Severity Index (ASI) indices at admission and they were more likely to use multiple substances more often. They were more likely than users of alcohol or other drugs to complete treatment, but this varied by drug. At follow-up 90 days after discharge, club drug users continued to report more ASI problems. Profiles of these clients show that ecstasy use has spread beyond the club culture, as indicated by the changes in client demographics over time. GHB clients presented a mixed picture of severe problems at admission and good response to treatment. Hallucinogen clients were young and less likely to complete treatment, while Rohypnol users were on the Texas-Mexico border. The methamphetamine epidemic has resulted in increased admissions, and the proportion of “Ice” smokers has increased. However, methamphetamine clients were less likely to complete treatment and their higher level of problems at admission and follow-up are of concern. Of special note are the indications of co-occurring problems and the need for both mental health and substance dependence treatment for some clients.     

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression

BackgroundKetamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor–dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.MethodsResting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.ResultsA reduction in Montgomery–Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.ConclusionsThese preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.     

右美托咪啶复合小剂量氯胺酮用于肠镜下治疗的效果观察

目的：观察右美托咪定复合小剂量氯胺酮用于肠镜下治疗的安全性及可行性。方法选取需行肠镜下治疗患者60例,随机分为2组,每组30例。其中D组患者使用右美托咪定复合氯胺酮麻醉;P组患者使用异丙酚复合芬太尼麻醉。观察并记录2组患者注药前（ T1）、置入肠镜（ T2）、操作结束（ T3）、苏醒（ T4）等时点的MAP、HR、SPO2,以及操作总时间（ T）和完全清醒需要的时间（ Tw ）;记录有无低血压、缓慢心率、呼吸抑制等不良反应。结果 D组患者术前、术中、术后、苏醒时MAP、HR、SPO2变化较P组平稳,且完全清醒时间要短于P组,低血压、缓慢心率和呼吸抑制发生率也要低于P组,2者比较差异均有差异性（ P值均小于0.05）。结论对于肠镜下治疗需要较长时间镇静麻醉的手术,使用右美托咪定复合小剂量氯胺酮可以稳定患者术中的生命体征,且苏醒时间和苏醒质量优于异丙酚复合阿片麻醉,是一种比较安全理想的麻醉方式。     

硬膜外麻醉辅助氯胺酮复合丙泊酚用于乳腺癌根治术

目的观察硬膜外麻醉辅助氯胺酮复合丙泊酚用于乳腺癌根治术的效果及安全性。方法40例ASAⅠ～Ⅱ级择期硬膜外阻滞下实施乳腺癌根治术的患者,随机分成两组,每组20例。Ⅰ组:氟哌啶加杜冷丁分次静脉注射;Ⅱ组:氯胺酮复合丙泊酚微量注射泵连续静脉输注。Ⅰ组静注氟哌啶0.05mg/kg、杜冷丁1～1.5mg/kg,必要时追加剂量1～2次;Ⅱ组丙泊酚-氯胺酮以质量比2:1配成混合液(PK液),按丙泊酚剂量2～4mg/kg·h剂量微量注射泵连续静脉输注,根据手术进程及病人的反应调整给药速度,于手术结束前15min停止输注。术中监测心率(HR)、心电图(ECG)、血压(BP)、脉搏血氧饱和度(SPO2),同时观察麻醉效果及呼吸抑制情况,有无恶心、呕吐,眼球震颤、复视、幻觉以及记录清醒时间。术后24h记录术中有无恶梦、知晓和其他异常心理,询问病人对此麻醉方式的满意程度。结果两组患者血压、心率变化无显著性差异(P>0.05)。麻醉效果:Ⅱ组优于Ⅰ组。出现呼吸抑制:Ⅰ组6例,Ⅱ组无,两组差异显著(P<0.05)。恶心及呕吐:两组都无。麻醉恢复:Ⅰ组唤之即醒,Ⅱ组手术结束10～15min唤之能睁眼,但有多语、无力、头晕等现象。病人满意率:Ⅰ组8例,Ⅱ组18例,两组间差异显著(P<0.05)。结论硬膜外麻醉辅助氯胺酮复合丙泊酚用于乳腺癌根治术麻醉效果佳,生命体征平稳,不良反应少,安全性好。