Simultaneous separation of different types of amphetamine and piperazine designer drugs by capillary electrophoresis with a chiral selector

The recent emergence of a new class of piperazine-type compounds has brought about the need for laboratory screening methods for both seized drugs and toxicological samples. These piperazine compounds, which include 1-benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP), exhibit comparable physiological effects and can be substituted for the classic amphetamine-type drugs. We have optimized a chiral capillary electrophoresis (CE) separation that detects a set of 6 piperazine and 4 chiral amphetamine compounds in under 23 min using a 200 mM phosphate buffer at a pH = 2.8 with 20 mM hydroxypropyl- beta-cyclodextrin (HPbeta3CD). In addition to the above compounds, a series of "clandestine" BZP diHCl samples were also analyzed using this method to assess the ruggedness of the procedure. The novel CE separation was tailored to simultaneously detect these piperzine compounds in addition to amphetamine-type drugs. Distinct migration time and UV-spectral data were obtained for all compounds of interest.     

Natural Law: Practical Reason and Creative Information

With nine main theses that are interspersed with each other, this paper explores and articulates some of the most important questions in natural law theory. The theses include: I. In investigating facts, one finds reasons to choose an honest self-discipline; II. Deliberating, one finds reasons similarly directing one to other intrinsic goods; III. Taken integrally, these goods and principles acquire the force of moral precepts; IV. Those precepts, natural moral law, depict our nature (humanity) in its flourishing; V. Nature and natures are best explained by free, intelligent transcendent creation; VI. Creation and other gifts past and present deserve our gratitude; VII. Natural moral law and historical revelation are two channels of information; VIII. Secular and spiritual communities are distinct and respectfully self-governing; IX. Natural moral law defines human rights but rightfully extends beyond them.     

Identification and synthesis of some contaminants present in 4-methoxyamphetamine (PMA) prepared by the Leuckart method

The clandestine synthesis of ring and side chain modified phenylisopropylamines continues to be a major source of these drugs of abuse. One method used for the synthesis of the amphetamine and related compounds involves the treatment of the appropriate ketone with formamide or ammonium formate followed by acid hydrolysis of intermediate N-formyl derivative. In this paper the synthesis of 4-methoxyamphetamine (PMA, 1) by the Leuckart method is investigated. The identification by means of gas chromatography-mass spectrometry (GC-MS) of methoxy derivative of N-(beta-phenylisopropyl)benzaldimine 9, methoxy derivative of N-(beta-phenylisopropyl)benzyl methyl ketimine 5, 1-(4-methoxyphenyl)-N-(4-methoxybenzyl)-2-propanamine 10, (RR/SS) and (RS) 1-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 6a-6c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-methyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 7a-7c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-formyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 8a-8c in crude PMA, are reported. The identity of these compounds was confirmed by independent synthesis of reference compounds. The NMR, MS, IR data, stereochemistry and some chromatographic properties of synthesized compounds are discussed. Finally, the results of the GC-MS analysis of illicitly prepared tablets, containing PMA 1 and 4-methoxymethamphetamine (PMMA, 2), are outlined. The presence of 4-methoxydimethylamphetamine 11, 4-methoxyethylamphetamine 12, and 4-hydroxymethamphetamine 13 are reported in these tablets. The identity of 2, 11, and 12 was confirmed by their independent synthesis.     

Positive and negative ion mass spectrometry of tricyclic antidepressants

Positive electron impact (EI), positive chemical ionization (CI), and negative CI mass spectra of eight tricyclic antidepressants are presented. In the positive EI mode, peak(s) at m/z 193 and/or 195, which corresponded to the tricyclic nucleus, appeared for five compounds; a peak at m/z 58 was common to compounds having a gamma-dimethylaminopropyl group as their side chain. Molecular ions appeared for all compounds though they were very small in some compounds in the positive EI mode. In the positive CI mode, [M + H]+ quasi-molecular peaks appeared together with [M + C2H5]+ peaks in five compounds; the ion at m/z 196, which corresponded to the tricyclic nucleus also appeared in five compounds. In the negative CI mode with 1 Torr chamber pressure, [M - 1]- quasi-molecular ions were observed for all compounds except for lofepramine; [M + 43]- anions, which probably corresponded to [M + C3H4]-, appeared in five compounds; strong [M + Cl]- ions appeared in carpipramine and clocapramine. The anions due to the tricyclic nucleus also appeared in this mode. In the negative CI mode at low pressure (0.01 Torr), the spectra were generally similar to those in the 1 Torr negative CI mode. However, the cluster anions never appeared at the low pressure. Some data on extraction for some antidepressants from human urine and plasma, and their separation by gas chromatography, are also presented.     

高效液相色谱法测定人血清中安眠酮及其苯甲基羟化代谢物的浓度

本文建立了用反相高效液相色谱法(RP-HPLC)测定人血清中安眠酮及其苯甲基羟化代谢物-2-甲基-3[2-(羟甲基)-苯基]-4(3H)喹唑酮(Ⅰ)的浓度。安眠酮浓度在1-35μg/ml范围内呈直线相关(相关系数r=0.9980;回归方程y=0.06324x—0.1029),方法回收率平均为102.08±9.987(SD)％(n=5),检出限为1ng。其代谢物Ⅰ按原型安眠酮的线性浓度测定其相对量。本法为测定中毒者体内安眠酮及其代谢物Ⅰ的血浓度提供可行的手段。     

3种哌嗪类药物滥用研究进展

哌嗪类药物N-苄基哌嗪(BZP)、1-(3-氯苯基)哌嗪(mCPP)、1-(3-三氟甲基苯基)哌嗪(TFMPP)具有与MDMA相似的兴奋作用和致幻作用,成了迷幻药的替代品,在各国滥用的报道逐年增多。本文综述了3种哌嗪类药物在各国的管制、滥用情况、毒理作用、检测方法,希望为司法部门打击此类药物犯罪提供参考和借鉴。     

闭合性颅脑损伤后大鼠BAEP及脑损伤的动态变化

目的观察大鼠闭合性弥漫性颅脑损伤后脑干听觉诱发电位(BAEP)的动态改变及脑组织病理学变化,探讨BAEP在颅脑损伤后评估听觉功能障碍的价值。方法使用自制弹簧式小型生物打击机打击大鼠颅顶部,制造闭合性弥漫性轻型颅脑损伤模型。观察对照组以及伤后15min和1,3,6,12h及1,2,4,7,10,14,21d等时间点大鼠脑组织病理学改变,干/湿法检测脑组织含水量。分别于伤前、伤后各时间点以50Hz刺激率记录大鼠BAEP,对其结果进行比较。结果损伤后15min,BAEP的Ⅰ～Ⅴ、Ⅲ～ⅤIPL即较损伤前延长(P<0.05),至6～12h,Ⅲ、ⅤPL较损伤前延长。损伤后1～2d,Ⅲ、ⅤPL和Ⅰ～Ⅲ、Ⅰ～Ⅴ、Ⅲ～ⅤIPL均较损伤前显著延长(P<0.001),14d后BAEP逐渐恢复正常。伤后15min脑组织含水量开始升高,伤后1d达高峰,持续至4d后逐渐下降,至10d后降至正常水平。结论BAEP可作为闭合性弥漫性轻型颅脑损伤后听觉功能障碍的客观评价指标。     

Die unterschiedlichen rechtlichen Anforderungen an die Zulassung von Biomasseanlagen

Anl?sslich der Einführung des § 35 Abs. 1 Nr. 6 Baugesetzbuch (BauGB) n.F. durch das EAG-BauGB1 im Juli 2004 besch?ftigt sich der Beitrag mit den Zul?ssigkeitsvoraussetzungen für den Bau einer Biomasseanlage. Nach einer kurzen Einleitung (I.) und einer Definition des Begriffs Biomasse (II.) wird zun?chst die bauplanungsrechtliche Zul?ssigkeit von Biomasseanlagen er?rtert (III.), dann die immissionsschutzrechtliche Einstufung der Anlage (IV.), die Zul?ssigkeit der Verwendung bestimmter Stoffe in solchen Anlagen (V.), anlagenbezogene Vorschriften (VI.) und schlie?lich der Verbleib der durch die Anlage erzeugten Reststoffe (VII.).     

Chinese Practice in Public International Law: 2006 (II)

Continued from Part I published earlier this year, this partof the survey covers materials reflecting Chinese practice in2006 relating to: Fundamental principles of international law(Section IV; territorial integrity, including Taiwan issue andTibet issue, non-interference of internal affairs and friendlyco-operation); International law of recognition (Section V;recognition of States and governments); International peaceand security (Section VI; North Korea nuclear issue, Iraniannuclear issue, Darfur issue, Kosovo issue, Great Lake regionissue, Lebanon–Israel conflict issue and Middle East issue);Anti-terrorism (Section VII); Non-proliferation and disarmament(Section VIII; general policy, nuclear disarmament, Treaty onNuclear Non-Proliferation of Nuclear Weapons (NPT), ComprehensiveTest Ban Treaty (CTBT), Treaty on the Central Asia Nuclear WeaponFree Area, Security Assurances for non-nuclear-weapon States,Fissile Material Cut-off Treaty (FMCT), Bacteriological (Biological)and Toxin Weapons and on Their Destruction (BWC), Certain ConventionalWeapons (CCW), Ottawa Convention, Non-Proliferation of Weaponsof Mass Destruction (WMDs) and Missiles, Illicit Trade in SALW,UN Disarmament Commission, Conference of Disarmament (CD) andPrevention of an Arms Race in Outer Space (PAROS)); InternationalLaw on Territory and Frontier (Section IX; Diaoyu Islands, NanshaIslands, China–India Territorial and Frontier Dispute,China–Russia Frontier); International Law of the Sea (SectionX; UN Commission on the Limits of the Continental Shelf, Conservationof Marine Bio-diversity Beyond Areas of National Jurisdiction,Fishery, Convention on the Conservation of Antarctic MarineLiving Resource, Marine Navigation, Delimitation and DevelopmentDisputes with Japan in East China Sea, Principle of MaritimeDelimitation with Other Countries, Base Points of the ChineseTerritorial Sea and The Issue of Suyan Islet).     

Piperazine-like compounds: a new group of designer drugs-of-abuse on the European market

1-Aryl-piperazine compounds are, depending on their substituents, selective for certain serotonin receptors and together with their easy availability and their so-called legal status, this group of psychoactive compounds are potential designer drugs-of-abuse. Internet in that respect is an important source of information and distribution facilities. Because this development may have consequences for the interpretation of future clinical and forensic toxicological case studies, some analytical aspects of 1-benzyl-piperazine (BZP), 1-[4-methoxyphenyl]-piperazine (pMeOPP) and 1-[3-trifluoromethylphenyl]-piperazine (TFMPP) were studied. BZP was not detected by the AxSYM FPIA technology designed to determine amphetamine-like compounds, but had showed some cross reactivity with EMIT d.a.u.. The cross reactivities at 300 and 12,000ng/ml (RS)-amphetamine equivalents were 0.4 and 1.3%, respectively. Although BZP was not identified directly by the REMEDi HS Drug Profiling System, it can be detected by this HPLC/UV scanning system. Using GC/NPD without derivatisation, BZP, pMeOPP and TFMPP can be analysed for and applying GC/MS without or with acetylation or trifluoroacetylation, these compounds can be identified unambiguously. The usefulness of GC/NPD and GC/MS in this respect was demonstrated by the quantitative and qualitative analysis of the content of a capsule with the synthetic stimulant A2, which proved to contain 86.4mg of BZP.     

新型毒品1-（3-三氟甲基苯基）哌嗪的检验

目的建立新型毒品1-（3-三氟甲基苯基）哌嗪的检验方法。方法通过选择和优化建立了1-（3-三氟甲基苯基）哌嗪类毒品的GC／MS、GC／TSD定性定量分析条件。结果以建立的分析方法,知查获的片剂中含有1-（3-三氟甲基苯基）哌嗪,其含量为51．13％,GC／TSD最低检出线是10ng／mL。结论本文所建方法可以用于1-（3-三氟甲基苯基）哌嗪涉毒检材的检验鉴定。     

Identification of common impurities present in the synthetic routes leading to 4-methylthioamphetamine (4-MTA). Part II: Reductive amination and nitropropene route

In this paper the by-products arising during the synthesis of 4-methylthioamphetamine (4-MTA) by LiAlH(4) reduction of 1-(4-methylthiophenyl)-2-nitropropene (nitropropene route) and reductive amination of 4-methylthiophenyl-2-propanone in the presence of NaCNBH(4) are investigated. The identification of 4-methylthio derivatives of N-(β-phenylisopropyl)benzaldimine, 4-methylthio derivative of N-(β-phenylisopropyl)benzyl methyl ketimine, 1-(4-methylthiophenyl)-N-(4-methylthiobenzyl)-2-propanamine, (RS) and (SS/RR)-N,N-di-[β-(4-methylthiophenyl)isopropyl]amine, 4-methylthiobenzyl ether and methylthiobenzoic acid methyl ester as most prominent impurities in crude 4-MTA synthesised by reductive amination of 4-methylthiophenyl-2-propanone, is reported. Methylthio derivatives of 2-methyl-3-phenylaziridine, 2-benzylaziridine, and 4-methylthio derivative of BMK oxime as route-specific markers of nitropropene route leading to 4-MTA, were also characterized. The identity of these compounds was confirmed by their independent synthesis.     

Stages of postmortem formation of washerwoman's skin--results of systematic qualitative and quantitative experimental studies

The development of washerwoman's hands depends upon the length of submersion. Until now there have been no results published on the qualitative and quantitative time-related changes with regard to washer-woman's hands. The fingertips of 50 hands from 35 corpses were qualitatively examined at early postmortem (1-4 h after death). The quantitative investigations were confined to the tips of the middle fingers. Submersion of the hands in water at 37 degrees C was interrupted at intervals of 10 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 10 h and 24 h for a period of 30s-1 min. The width of three adjoining ridges of the skin were measured in three defined areas of the middle fingertips and photographs were taken. Quantitative results: No relevant differences were seen in the changes of the width of the skin ridges between the right and left hand after submersion in water; there was no specific difference between the sexes. During the soaking process the skin ridges influence each other. The age of the individual corpse has no influence on the change in width of the skin ridges. Concerning the qualitative test results, six time-limited stages could be classified: stage I: physiological dry state; stage II: softened state; stage III: swollen and compressed state; stage IV: partial wrinkle covering; stage V: epidermal lysis; stage VI: loss of relief outlines.     

Determination of synthesis route of 1-(3,4-methylenedioxyphenyl)-2-propanone (MDP-2-P) based on impurity profiles of MDMA

In our study 1-(3,4-methylenedioxyphenyl)-2-propanone (MDP-2-P or PMK) was prepared by two different routes, i.e. by oxidizing isosafrole in an acid medium and by 1-(3,4-methylenedioxyphenyl)-2-nitropropene reduction. The final product-MDP-2-P was subjected to GC/MS analysis. The intermediates and reaction by-products were identified and the 'route specific' impurities were established. The following impurities are the markers of the greatest importance: 1-(3,4-methylenedioxyphenyl)-1-propanone (compound 10, Table 2), 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-propanone (compound 11, Table 2) and 2,2,4-trimethyl-5-(3,4-methylenedioxyphenyl)-[1,3]dioxolane (compound 13, Table 2) (the 'oxidising isosafrole route') and N-cyclohexylacetamide (compound 3, Table 1), 3-methyl-6,7-methylenedioxyisoquinoline-1,4-dione (compound 15, Table 1) (the 'MDP-2-nitropropene reduction route'). Subsequently, MDMA was prepared by reductive amination of MDP-2-P using NaBH4 as reducing agent (so-called 'cool method'). Impurities were extracted with n-heptane under alkaline conditions. The impurity profiles were obtained by means of GC/MS, some reaction by-products were identified by means of the EI mass spectra including low energy EI mass spectra and 'route specific' impurities were established. 4-Methyl-5-(3,4-methylenedioxyphenyl)-[1,3]dioxolan-2-one (compound 22, Table 2), N-methyl-2-methoxy-1-methyl-2-(3,4-methylenedioxyphenyl)-ethaneamine (compound 18, Table 2), 3-methyl-6,7-methylenedioxyisoquinoline-1,4-dione (compound 15, Table 1) and N-cyclohexyloacetamide (compound 3, Table 1) were found to be the synthesis markers of greatest importance.     

Occupational exposure to hexavalent chromium. Final rule

The Occupational Safety and Health Administration (OSHA) is amending the existing standard which limits occupational exposure to hexavalent chromium (Cr(VI)). OSHA has determined based upon the best evidence currently available that at the current permissible exposure limit (PEL) for Cr(VI), workers face a significant risk to material impairment of their health. The evidence in the record for this rulemaking indicates that workers exposed to Cr(VI) are at an increased risk of developing lung cancer. The record also indicates that occupational exposure to Cr(VI) may result in asthma, and damage to the nasal epithelia and skin. The final rule establishes an 8-hour time-weighted average (TWA) exposure limit of 5 micrograms of Cr(VI) per cubic meter of air (5 [mu]g/cu m). This is a considerable reduction from the previous PEL of 1 milligram per 10 cubic meters of air (1 mg/10 cu m, or 100 [mu]g/cu m) reported as CrO3, which is equivalent to a limit of 52 [mu]g/cu m as Cr(VI). The final rule also contains ancillary provisions for worker protection such as requirements for exposure determination, preferred exposure control methods, including a compliance alternative for a small sector for which the new PEL is infeasible, respiratory protection, protective clothing and equipment, hygiene areas and practices, medical surveillance, recordkeeping, and start-up dates that include four years for the implementation of engineering controls to meet the PEL. The final standard separately regulates general industry, construction, and shipyards in order to tailor requirements to the unique circumstances found in each of these sectors. The PEL established by this rule reduces the significant risk posed to workers by occupational exposure to Cr(VI) to the maximum extent that is technologically and economically feasible.     

Positive and negative ion mass spectrometry of antiepileptic hydantoins and their analogs

Positive ion electron impact (PIEI), positive ion chemical ionization (PICI), and negative ion chemical ionization (NICI) mass spectra of seven compounds of hydantoins and their analogs are presented; their probable fragmentation modes are also presented. In the PIEI mode, intensities of molecular ions differed according to different compounds. Cleavage at outsides of both carbonyl groups was commonly observed for all compounds. In the PICI mode, all compounds showed [M + 1]+ quasi-molecular ions constituting the base peaks. In the NICI mode, [M - 1]- quasi-molecular anions were the base peaks except for trimethadione and paramethadione. All negative spectra showed anions at m/z 42 due to [NCO]-; these peaks seem useful for screening of antiepileptics. An extraction procedure for the anti-epileptics from human urine or plasma, and their separation by gas chromatography (GC), are also presented to serve for their actual identification by GC/mass spectrometry.     

Numerical density of mu opioid receptor expressing neurons in the frontal cortex of drug related fatalities

In animal and cell culture experiments, chronic morphine treatment has been followed by 'up'- as well as 'down-regulation' of the mu opioid receptor (mu OR) number. The present postmortem morphometric study of morphine-related fatalities of drug addicts (n=12, and 22-35 years old, with blood unconjugated morphine levels from 27.1 to 458 ng/ml, m.v. 198.5 ng/ml) versus a non-addicted control group (n=13 and 10-44 years old) was intended to examine whether chronic opiate exposure affects the numerical density of mu OR expressing neurons in the human neocortex (area 10 according to Brodmann). For the immunohistochemical procedure, thick (100 microm) vibratome sections were incubated with a monoclonal antibody against the mu OR [Arvidsson et al., J. Neurosci. 15 (1995) 3328] and immunoreactive sites were visualized using an immunoperoxidase protocol. The numerical densities of mu OR-expressing and Nissl-stained neurons were assessed morphometrically (camera lucida-drawings). In both collectives, the anti-mu OR immunoreactivity was mainly found in pyramidal neurons of layers (L) II/III and V and in multiform neurons of L VI. In the drug-related fatalities and the control group, the density of neurons expressing mu OR protein was similar, amounting for 2698 +/- 153 and 2688 +/- 172/mm(3), respectively. These findings extend the binding studies of opioid ligands in postmortem brains of heroin addicts [Gabilondo et al., Psychopharmacology 115 (1994) 135] revealing similar receptor densities and affinities by showing no difference in the density of mu OR-positive neurons.     

略论当前我国法学教育体制存在的问题

我国的法学教育体制，特别是法学学位体系和人才培养模式，正面临着急迫的问题与挑战，亟待解决。其具体表现在如下几个方面：法学学位项目层次和种类过多；法学学位体系之间相互交叉，职责界限不清，管理混乱；缺乏法学主学位，过分重视高学历法学教育，人才培养同质化严重；学位教育项目与法律职业准入相互脱节；法学教育规模急剧扩大与确保法学教育质量之间矛盾增大；课程体系与课程设置不合理，法学各专业教学特色不明显；法学人才的招录体制和分配去向存在着地区间严重不平衡；全球化法学教育的挑战与国内法律人才国际视野的局限性。     

大鼠死后脑组织的傅里叶变换红外光谱变化

目的应用傅里叶变换红外（Fourier transform infrared．FTIR）光谱技术分析大鼠死后脑组织随死亡时间推移的化学变化过程,为死亡时间推断的研究提供新的途径与数据。方法大鼠断颈处死后置于（30±2）℃环境下,在不同时间点提取大鼠脑皮质．运用FTIR光谱仪检测不同化学基团的变化。结果随着死亡时间的推移,大鼠脑组织FTIR光谱的主要吸收峰峰位没有明显变化．而其峰强有明显差异：（1）与核酸有关的谱带的相对峰强呈明显下降趋势;（2）酰胺Ⅰ、Ⅱ的峰强比（I1647/I1541）呈下降趋势;（3）1456和1398cm^-1谱带的峰强各自呈下降和上升趋势;（4）2852、2871、2923和2958cm^-1谱带的峰强相对于1647cm^-1而言．呈上升趋势。结论脑组织可以作为FTIR光谱技术分析死亡时间的适用检材。     

Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method

The synthesis of the designer drug 4-methylthioamphetamine (4-MTA) has been carried out using the well-known Leuckart reaction in four versions. The treatment of 4-methylthiophenylacetone with formamide, mixture of formamide/formic acid, ammonium formate, and mixture of ammonium formate and formic acid followed by acid hydrolysis brought about the formation of 4-MTA contaminated with a number of impurities. The gas chromatography mass-spectrometry (GC-MS) analysis of the reaction mixtures allowed identification of the most prominent impurities, such as diasteromers of N,N-di-[β-(4-methylthiophenyl)isopropyl]amine, N,N-di-[β-(4-methylthiophenyl)isopropyl]methylamine, N,N-di-[β-(4-methylthiophenyl)isopropyl]formamide, the Schiff bases derived from 4-MTA and 4-methylbenzaldehyde (benzaldimine) and 4-methylthiophenylacetone (ketimine) as well as some heterocycles: 4-methyl-5-(4'-methylthiophenyl)pyrimidine, 4-(4'-methylthiobenzyl)pyrimidine, 2,6-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine, 2,4-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine. The correctness of identification was confirmed by independent synthesis of these compounds. Each synthesized reference compound was characterized by means of MS, (1)H and (13)C NMR, and IR methods. The stereochemistry of (RR/SS) diasteromer of N,N-di-[β-(4-methylthiophenyl)isopropyl]amine was confirmed by a crystallographic method.