合成卡西酮类物质依赖性评价及相关机制研究进展

21世纪初,大量的合成卡西酮流入非法市场,通常以“浴盐”、“植物性食品”的形式在网上售卖,并标有“非供人使用”标签.该物质种类繁多、衍生速度快,其结构或药理学性质与可卡因或甲基苯丙胺类似,经常被滥用,且对个人健康和社会稳定造成极大的影响.为进一步评估合成卡西酮类物质的滥用潜力及其成瘾机制,本文从自主给药实验、药物辨别实...     

Qualitative analysis of seized synthetic cannabinoids and synthetic cathinones by gas chromatography triple quadrupole tandem mass spectrometry

Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized‐drug analysis is mainly performed by gas chromatography‐electron ionization‐mass spectrometry (GC‐EI‐MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized‐substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography‐triple quadrupole‐tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized‐drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.     

An LC‐MS/MS methodological approach to the analysis of hair for amphetamine‐type‐stimulant (ATS) drugs,including selected synthetic cathinones and piperazines

Amphetamine‐type‐stimulants (ATS) are the second most commonly used group of illicit drugs worldwide. However, in the last few years, new psychoactive substances (NPS) with stimulant effects have appeared on the illegal market, which are not detected with traditional analytical methods. A liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for the determination in hair of classic ATS (amphetamine, methamphetamine, 3,4‐methylenedioxymethamphetamine and 3,4‐methylenedioxyamphetamine), synthetic cathinones (methylone, methedrone, mephedrone, 3,4‐methylenedioxypyrovalerone, (±)‐4‐fluoromethamphetamine and 4‐fluoromethcathinone), synthetic piperazines (1‐(3‐chlorophenyl)piperazine (mCPP) and 3‐trifluoromethylphenylpiperazine), and medicines (trazodone and phenazone) that produce mCPP as a metabolite, was developed and fully validated. Hair samples (30 mg) were incubated in acid methanol (0.1% HCl) and extracted by a mixed‐mode solid‐phase extraction. Chromatographic separation was performed using an Atlantis T3 (3 µm; 2.1x50 mm) analytical column, and ammonium formate 2 mM pH 3 and acetonitrile as mobile phase. The method was validated, including selectivity (no endogenous or exogenous interferences); linearity (2–20 to 2000–4000 pg/mg); limits of detection (0.2 to 5 pg/mg) and quantification (2 to 20 pg/mg); accuracy (93.4–109.4% of target concentration); imprecision (%CV<11.6%); extraction recovery (40.5–92.1%); matrix effect (24.1–227.2%); process efficiency (9.8–165.7%) and stability in the autosampler (‐14.5% of loss). The method was applied to the analysis of 16 hair samples. Amphetamine (n=7; 69.1–777.1 pg/mg), methamphetamine (n=3; 120.4–1,538.9 pg/mg), MDA (n=2; 27.8–135.4 pg/mg) and MDMA (n=8; 73.4–3,654.5 pg/mg) were found. Moreover, 10 positive results for mCPP were detected (341.7–>4000 pg/mg); however, in all cases trazodone identification (2085.3–>4000 pg/mg) probed a licit origin of mCPP. Copyright © 2016 John Wiley & Sons, Ltd.     

二极管阵列检测技术在中药化学分析中的应用

本文简要介绍了二极管阵列检测技术在中药化学分析中的几方面应用实例。峰纯度、色谱峰光谱一致性检测是高效液相色谱分析方法的可靠性和适用性评价的较先进的手段。     

Potentialities of ITP-CZE method with diode array detection for enantiomeric purity control of dexbrompheniramine in pharmaceuticals

The present work illustrates potentialities of on-line combined isotachophoresis-capillary zone electrophoresis (ITP-CZE) separation techniques coupled with on-capillary diode array detector (DAD) for enantiomeric purity testing of drugs in pharmaceuticals. The general advantages of the proposed method are its (i) high selectivity, (ii) low concentration limit of detection (LOD) obtainable, (iii) enhanced sample loadability, and (iv) enhanced reliability. For separation of brompheniramine (BP) enantiomers, serving as model analytes, carboxyethyl-β-cyclodextrin (CE-β-CD) was appropriate chiral selector providing complete enantioresolution. Given by a high sample load capacity (30 μl sample injection volume) and preconcentration of the analytes in ITP stage, concentration LOD of levobrompheniramine (LBP), serving as model impurity, was 2.5 ng/ml (8 × 10⁻⁹ mol/l). Such separation and detection conditions enabled to easily determine LBP in samples containing a 10³ excess of dexbrompheniramine (DBP). DAD detection in comparison with single wavelength detection can enhance value of analytical information when analytes and interferents have different spectra (distinguishing impurities in analyte zone, confirmation of migration positions of migrants). In this context purity of BP zones was confirmed with higher reliability in pharmaceutical sample. Moreover, distinguishing the trace analyte signal superposed on the baseline noise was provided with sufficient reliability (for this purpose the background correction and smoothing procedure had to be applied to the raw DAD spectra). Successful validation and application of the proposed ITP-CZE-DAD method suggest its routine use for the enantiomeric purity testing of pharmaceuticals.     

A stability-indicating HPLC assay with diode array detection for the determination of a benzylpenicillin prodrug in aqueous solutions

The aim of this study was to develop a stability-indicating HPLC assay for the determination of penethamate (PNT), an ester prodrug of benzylpenicillin (BP), in aqueous solutions. The method was validated by subjecting PNT to forced decomposition under stress conditions of acid, alkali, water hydrolysis and oxidation. A quenching solution was developed to limit degradation to negligible levels before and during the analysis. Both PNT and BP were simultaneously determined and separated in presence of degradation products on a C₁₈ column using a mobile phase consisting of methanol–acetonitrile–acetate buffer. Different degradation products were formed in the stress conditions. The peak purity indexes of PNT and BP obtained by diode array detection were >0.999, confirming the absence of other co-eluting substances. The assay was linear for both analytes in the concentration range 1–100 μg mL⁻¹. The LOD and LOQ of PNT were 0.03 and 0.09 μg mL⁻¹ respectively. Degradation of PNT followed pseudo-first-order kinetics with t_1/2 of 43.6 min at pH 2.01 and 4.2 min at pH 9.31. In addition, the absence of BP in the acidic solutions of PNT emphasises the futility of monitoring BP to assess the stability of PNT. In conclusion, the assay is rapid and stability-indicating with adequate precision and accuracy, and in conjunction with the quenching solution, can be used for stability studies of PNT with simultaneous quantitation of BP. The degradation studies provide useful information for formulation development of PNT.     

RP-HPLC二极管阵列检测器对阿替洛尔注射液质量的研究

目的：建立阿替洛尔注射液含量及有关物质的RP-HPLC测定法。方法：采用Shimadzu ODS色谱柱，以甲醇-磷酸二氢钾-庚烷磺酸钠（400：600：1．3）为流动相，检测波长275nm。结果：阿替洛尔峰与各成分的分离度及检出灵敏度满足测定要求。阿替洛尔峰最小检出量为2ng（S／N=3）。二极管阵列检测器检测阿替洛尔峰纯度〉99．99％。结论：本法简便，专属，准确。     

Induction of immediate early genes expression in the mouse striatum following acute administration of synthetic cathinones

BackgroundSynthetic cathinones (SCs) form one of the most prominent group of the New Psychoactive Substances. SCs enhance central dopaminergic and noradrenergic neurotransmission, and are used as substitutes for illicit psychostimulants, namely cocaine, amphetamine, and methamphetamine. Changes in the expression of immediate early genes (IEGs) in the striatum underlie the addictive potential of drugs of abuse belonging to distinct pharmacologic groups. This work was aimed to assess the impact of acute administration of the prominent SCs on the mRNA levels of IEGs in the mouse striatum.MethodsEffects of 3,4-MDPV, 2,3-MDPV, α-PVP, PV8, PV9, methcathinone (MC) and 3-fluoromethcathinone (3-FMC) on the mRNA levels of ten IEGs, one and two hours after exposure, were measured in the mouse striatum using the quantitative RT-PCR technique.ResultsAll SCs used in the study produced increased mRNA levels of the following IEGs: Areg, c-fos, Csrnp1, Dusp1, Dusp14, Egr2, Egr4 and FosB. Additionally, the majority of SCs increased the expression of Homer1 and c-jun. The magnitude of observed changes varied by the drug, analyzed gene and, in many cases, by time after administration.ConclusionsThis study demonstrates that SCs increase the expression of IEGs in the mouse striatum, which may lead to a plethora of effects, as proteins encoded by the analyzed genes are involved in diverse actions, including an acute response to the drug and the neuroplasticity underlying the development of addiction.     

Determination of orphenadrine plasma levels using HPLC with diode array detection and a novel solid-phase extraction procedure in psychiatric patients

Orphenadrine is an antimuscarinic agent mainly used for the treatment of parkinsonism and to alleviate the neuroleptic syndrome induced by antipsychotic drugs.     

HPLC‐MS/MS combined with membrane‐protected molecularly imprinted polymer micro‐solid‐phase extraction for synthetic cathinones monitoring in urine

Synthetic cathinones are a type of drug belonging to group of new psychoactive substances (NPSs). The illicit market for these substances is characterized by the continuous introduction to the market of new analogs to evade legislation and to avoid detection. New screening and confirmation assays are therefore needed, mainly in forensic/clinical samples. In the current development, a porous membrane‐protected, micro‐solid‐phase extraction (μ‐SPE) has been developed for the assessment of several cathinones in urine. The μ‐SPE device consisted of a cone‐shaped polypropylene (PP) porous membrane containing the adsorbent (molecularly imprinted polymers, MIPs, synthesized for the first time for this class of drugs). MIPs were prepared using ethylone and 3‐methylmethcathinone (3‐MMC) as templates, ethylene glycol dimethacrylate (EGDMA) as a functional monomer, divinylbenzene (DVB) as a cross‐linker, and 2,2´‐azobisisobutyronitrile (AIBN) as an initiator. The prepared ethylone‐based MIP and 3‐MMC‐based MIP have been fully characterized and evaluated as new selective adsorbents for μ‐SPE. Cathinones separation/determination was performed by high performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Optimum loading conditions (pH 5.0, loading for 4.0 minutes under orbital‐horizontal shaking at 200 rpm) and elution conditions [2.0 mL of 75:20:5 heptane/2‐propanol/ammonium hydroxide and ultrasounds assistance (37 kHz, 325 W) for 4.0 minutes] were found for ethylone‐based MIP. Validation (intra‐day and inter‐day precision and analytical recovery) showed RSD values lower than 9 and 10% for intra‐day and inter‐day precision, and within the 88%–101% range for intra‐day and inter‐day analytical recovery.     

Diode array detection of low level co-eluting species in high-performance liquid chromatography

A simple and sensitive method for detecting low levels (0.5 and 1.0%, w/w) of co-eluting species in HPLC has been developed. This method is based on the subtraction of normalized peak up-slope and down-slope spectra from that of the apex. Visual inspection of the resultant “difference spectra” allows for a qualitative judgement regarding the integrity of the peak under consideration.     

Simultaneous determination of eight active components in Chinese medicine 'JiangYaBiFeng' tablet by HPLC coupled with diode array detection

An effective, accurate and reliable method was developed for the simultaneous separation and determination of eight active components (baicalin, baicalein, sophoricoside, rutin, quercetin, genistein, pargyline and hydrochlorothiazide) in Chinese medicine 'JiangYaBiFeng' tablet (JYBF tablet) by high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD). Due to the different UV characteristic of these components, different wavelengths were selected for analysis of different analytes, such as 210nm for pargyline, 256nm for sophoricoside, rutin, quercetin and genistein, and 280nm for baicalin, baicalein and hydrochlorothiazide. Excellent linear behaviors over the investigated concentration ranges were observed with the values of R(2) higher than 0.9990 for all analytes. The recovery rates and relative standard deviation (RSD) for all analytes at three different concentrations were 94.9-104.7% and 1.23-3.00%, respectively. The validated method was successfully applied to the simultaneously determination of these active components in 'JiangYaBiFeng' tablet from different production batches, indicating that the proposed method in this paper was particularly suitable for the routine analysis of JYBF tablet and its quality control.     

Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market

The use of hyphenated analytical techniques in forensic drug screening enables simultaneous identification of a wide range of different compounds. However, the appearance of drug seizures containing new substances, mainly new psychoactive substances (NPS), is steadily increasing. These new and other already known substances often possess structural similarities and consequently they exhibit spectral data with slight differences. This situation has made the criteria that ensure indubitable identification of compounds increasingly important. In this work, 6 new synthetic cathinones that have not yet appeared in any Swedish drug seizures were synthesized. Their chemical structures were similar to those of already known cathinone analogs of which 42 were also included in the study. Hence, a total of 48 synthetic cathinones making up sets of homologous and regioisomeric compounds were used to challenge the capabilities of various analytical techniques commonly applied in forensic drug screening, ie, gas chromatography–mass spectrometry (GC–MS), gas chromatography–Fourier transform infrared spectroscopy (GC–FTIR), nuclear magnetic resonance (NMR), and liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC–QTOF–MS). Special attention was paid to the capabilities of GC–MS and GC–FTIR to distinguish between the synthetic cathinones and the results showed that neither GC–MS nor GC–FTIR alone can successfully differentiate between all synthetic cathinones. However, the 2 techniques proved to be complementary and their combined use is therefore beneficial. For example, the structural homologs were better differentiated by GC–MS, while GC–FTIR performed better for the regioisomers. Further, new spectroscopic data of the synthesized cathinone analogs is hereby presented for the forensic community. The synthetic work also showed that cathinone reference compounds can be produced in few reaction steps.     

A new automated assay for the detection of synthetic urine in drug testing

Urine drug testing can be subject to attempts to dilute, adulterate, or substitute the specimen. Substitution may involve the use of commercially available synthetic urine. Current laboratory methods to detect specimen validity often fail to detect these products. We evaluated a new automated assay designed to detect synthetic urine. We determined that the assay met performance requirements and accurately identified five commercially obtained products as synthetic urine while not identifying known normal urine as synthetic. However, in a group of 843 patient urine samples, 40 of the 46 urine samples identified as “synthetic” were samples with creatinine <50 mg/dL. Fourteen of the 40 were actually positive for drugs of abuse. We conclude that the test is analytically valid but clinically limited. We recommend that it be used in conjunction with other indicators of synthetic urine. We suggest a scheme that would achieve this, and reporting terminology that would reflect the limits of the analysis.     

毛细管电泳间接紫外法分离分析海藻和酱油中游离氨基酸方法研究

目的 建立一种快速检测海藻和酱油中游离氨基酸的毛细管电泳间接紫外法分离分析方法。方法 在分离电压为-20 kV,毛细管柱温25 ℃的条件下,40 mmol.L&lt;sub&gt;-1&lt;/sub&gt;三羟甲基氨基甲烷(Tris)为分离缓冲液,20 mmol.L&lt;sub&gt;-1&lt;/sub&gt;烟酸为背景添加剂(NaOH调pH 11.00),0.015％(w/v) 溴化己二甲铵(HDB)为电渗流(EOF)反转剂,考察分离缓冲液pH,浓度,HDB浓度,电压等参数对分离的影响,在最佳优化条件下13分钟内13种未衍生氨基酸得到基线分离。结果 方法线性良好(r≥0.9972),日内及日间精密度分别低于4.25%和7.41%,加标回收率为94.6％-105.5％。建立的方法成功应用于海藻和酱油中游离氨基酸的定性定量分析。结论 结果表明,所开发的方法可用于快速测定不同样品中游离氨基酸的组成及含量,为海藻和酱油样品中游离氨基酸的快速检测奠定基础。