Synthesis and in vitro anti-inflammatory activity of novel benzo[d] imidazolyl dihydrospiro[indoline-3,1′-isoindole]-2,4′,7′-triones

Synthesis of novel benzo[d]imidazolyldihydrospiro[indoline-3,1′-isoindole]-2,4′,7′-triones has been described. The key intermediate 2-[(2-sulfanyl-1H-benzo[d]imidazol-5-yl)amino]acetic acid is obtained by reacting 5-amino-2-mercapto benzimidazole and chloroacetic acid. The three-component reaction of 2-[(2-sulfanyl-1H-benzo[d]imidazol-5-yl)amino]acetic acid with isatin and 1,4-benzoquinone in the presence of 10 mol% of L-proline at ambient temperature afforded 2′-(2-mercapto-1H-benzo [d] imidazol-5-yl)-3′,3a′-dihydrospiro[indoline-3,1′-isoindole]-2,4′,7′(2′H,7a′H)-triones. All the synthesized compounds were evaluated for in vitro anti-inflammatory activity.     

Fatally injured drivers in Norway 2005–2015—Trends in substance use and crash characteristics

Objective: Norway introduced a “Vision Zero” strategy in 2001, using multiple approaches, aiming toward a future in which no one will be killed or seriously injured in road traffic crashes (RTCs). Official statistics show that the number of fatally injured road users has declined substantially from 341 deaths in 2000 to 117 in 2015. In-depth crash investigations of all fatal RTCs started in Norway in 2005. The aim of this study was to investigate whether fatal crash characteristics, vehicle safety features, and prevalence of drugs and/or alcohol among fatally injured drivers and riders has changed during 2005–2015, accompanying the reduction in road fatalities.

Methods: Data on all car/van drivers and motorcycle/moped riders fatally injured in RTCs during 2005–2015 were extracted from Norwegian road traffic crash registries and combined with forensic toxicology data.

Results: The proportion of cars and motorcycles with antilock braking systems and cars with electronic stability control, increased significantly during the study period. The prevalence of nonuse of seat belts/helmets and speeding declined among both fatally injured drivers and riders. In addition, the prevalence of alcohol declined, though no significant change in the total prevalence of other substances was noted.

Conclusion: The observed changes toward more safety installations in cars and motorcycles and lower prevalence of driver-related risk factors like alcohol use, speeding, and nonuse of seat belts/helmets among fatally injured drivers/riders may have contributed to the decrease in road traffic deaths.     

北京市城市河流中精神活性物质的污染水平及环境风险

为评价北京市城市河流地表水体中5种精神活性物质〔METH(甲基苯丙胺)、AMP(苯丙胺)、KET(氯胺酮)、EPH(麻黄碱)和HA(羟亚胺)〕的环境风险,通过对固相萃取柱(Oasis HLB、Oasis MCX、Oasis WAX和Oasis PRiME HLB)类型、水样酸化、洗脱剂类型及体积等条件的确定,建立了同时测定水环境中精神活性物质的固相萃取-液相色谱-质谱(SPE-LC-MS/MS)联用方法,并对北京市城市河流地表水体中5种精神活性物质的质量浓度水平进行了调查,采用RQ(风险熵)法进行了风险评价. 结果表明,在水样未酸化条件下,Oasis MCX柱对精神活性物质的回收率最高,使用含5%(V/V)氨水的甲醇作为洗脱液,5种精神活性物质的回收率可以达到81.8%~91.1%. 地表水水体基质加标结果表明,5种精神活性物质的加标回收率均大于75.5%,相对标准偏差均小于10.0%. 方法检出限为0.30~0.80 ng/L,定量限为1.00~2.68 ng/L. 北京市7条城市河流中5种精神活性物质的质量浓度在1.00~99.51 ng/L之间. EPH在所有采样点均被检出且质量浓度较高,ρ(EPH)平均值为22.79 ng/L;ρ(AMP)相对较低,在1.54~11.23 ng/L之间,但AMP检出率为97.06%;ρ(METH)较高,平均值为14.63 ng/L,最高值(99.51 ng/L)出现在坝河. 研究显示,北京市地表水中5种精神活性物质的RQ均小于0.1,表明其可能的环境风险较低,但由于精神活性物质本身具有生物活性,它们对城市河流水生生态系统产生的潜在危害不容忽视.      

兽药类环境内分泌干扰效应及评价研究进展

兽药在保障动物健康、提高畜禽产品质量尤其在畜牧业集约化发展等方面起着至关重要的作用,然而兽药和饲料添加剂的大量使用成为生态环境污染和人体健康损害的一个重要因素。研究表明许多抗生素类和激素类兽药是典型的环境内分泌干扰物,通过多种方式干扰生物体雄激素、雌激素、甲状腺激素等内分泌过程,产生内分泌干扰效应。本文介绍了典型兽药的污染现状及其内分泌干扰效应研究最新进展;以环境内分泌干扰物的最新研究方法为基础,较全面地评述了可用于兽药类内分泌干扰物的快速筛选、检测及评价方法,并对该领域未来研究提出了展望和建议,以期为环境和农业等管理部门制定兽药的使用、排放、管理政策提供科学依据。     

Predicting categories of drugs used by suspected drug-impaired drivers using the Drug Evaluation and Classification Program tests

Objective: The purpose of this study was to statistically determine which combination(s) of drug-related signs and symptoms from the Drug Evaluation and Classification (DEC) protocol best predict the drug category used by the suspected drug-impaired driver.

Methods: Data from 1,512 completed DEC evaluations of suspected impaired drivers subsequently found to have ingested central nervous system (CNS) depressants, CNS stimulants, narcotic analgesics, and cannabis were analyzed using a multinomial logistic regression procedure. A set of evaluations completed on drug-free subjects was also included. The relative importance of clinical, behavioral, and observational measures in predicting drug categories responsible for impairment was also examined.

Results: Thirteen drug-related indicators were found to significantly contribute to the prediction of drug category, including being under the care of a doctor or dentist, condition of the eyes, condition of the eyelids, mean pulse rate, assessment of horizontal gaze nystagmus (HGN), convergence, performance on the One Leg Stand (OLS) Test, eyelid tremors, pupil size in darkness, reaction to light, presence of visible injection sites, systolic blood pressure, and muscle tone. Indicators related to the appearance and physiological response of the eye contributed the most to the prediction of drug category, followed closely by clinical indicators and performance on the psychophysical tests.

Conclusions: The findings from this study suggest that drug recognition experts (DREs) should be careful to review a set of key signs and symptoms when determining the category of drug used by suspected drug-impaired drivers. Drug use indicators related to the appearance and physiological response of the eye were found to contribute the most to the prediction of the drug category responsible for the impairment. These results could help form the basis of a core set of indicators that DREs could initially consult to form their opinion of drug influence. This in turn may enhance the validity, effectiveness, and efficiency of drug detection and identification by DREs and lead to a more effective and efficient DEC program, improved enforcement of drug-impaired driving, and greater acceptance of the DEC program by the courts.     

北京市水环境中精神活性物质污染特征

为评价北京市水环境中精神活性物质的污染水平和生态环境风险,利用高效液相色谱-质谱联用法检测了该地区地表水和地下水中6种典型精神活性物质[甲基苯丙胺(METH)、苯丙胺(AMP)、氯胺酮(KET)、麻黄碱(EPH)、甲卡西酮(MC)和羟亚胺(HY)]的质量浓度.结果表明,北京市地表水中共检测出3种目标药物,其质量浓度范围为低于检出限n.d.~70.9ng·L~(-1).EPH的检出频率和质量浓度平均值最高,分别为42%和10.1 ng·L~(-1);其次为METH,检出频率为25%,质量浓度平均值为1.8 ng·L~(-1).地下水样品中只检测到了AMP,检出频率21%,质量浓度水平在n.d.~2.2 ng·L~(-1)之间.与国内外其他研究相比,北京市水环境中精神活性物质的污染浓度总体处于较低水平.METH和EPH浓度最高值均出现在北京市第二大排污河和南城主要污灌渠凉水河.风险评估结果显示,北京市地表水中6种目标药物的风险熵值均小于0.10,表明存在较低的环境风险,但考虑到精神活性物质具有较强的生物活性,它们对水生生态系统的长期和综合风险值得关注.     

Screening for Selected Human Pharmaceuticals and Cocaine in the Urban Streams of Manaus,Amazonas, Brazil

Pharmaceuticals and illicit drugs are contaminants that are generally ubiquitous in wastewater treatment plant effluents with their release into the environment being well understood in North America, Europe, and Asia. There is, however, less information on the release of human pharmaceuticals and illicit drugs from regions undergoing rapid land use, economical, and social changes, such as Brazil. This encompasses many areas in the tropical zone where releases of emerging contaminants may impact pristine, bio‐diversity rich ecosystems. In this study, the occurrence of human pharmaceuticals and the illicit drug cocaine was determined in the Rio Negro and two of its tributaries that receive large amounts of untreated sewage, the Igarapé Mindu and the Igarapé do 40, passing through the city of Manaus, Brazil. In addition to cocaine and its metabolite, benzoylecognine, propranolol, diclofenac, amitriptyline, carbamazepine, carbamazepine‐epoxide, citalopram, metoprolol, carisoprolol, and sertraline were all detected in two urban tributaries at low ng/l concentrations similar to those typically found in urban surface waters. Concentrations in the Rio Negro were typically lower than detection limits due to the large level of dilution, although traces of a range of pharmaceuticals were detected in the Rio Negro in proximity of the confluence of the urban streams. The data represent new information on the emissions of pharmaceuticals from a newly industrialized region of Brazil.     

在线固相萃取-液相色谱串联质谱法测定污水厂尾水中6种酸性药物

建立了大体积在线固相萃取-液相色谱串联质谱（Online-SPE-LC-MS）检测污水厂尾水中6种酸性药物的方法。10 mL水样采用0.45 μm微孔滤膜过滤后经自动进样器直接在线上样,经Atlantis T3柱（100 mm×4.6 mm×3 μm）富集,Atlantis T3柱（100 mm×2.1 mm×2.6 μm）色谱分离,ESI-/ESI+源同步切换扫描,多反应监测（MRM）模式对布洛芬、酮洛芬、双氯芬酸钠、吲哚美辛、苯扎贝特、卡马西平进行同时定量分析。基于外标法和标准加入法进行分析以消除基质效应。结果显示,6种酸性药物在0.1~200 ng/L范围内线性相关性较好（r≥0.996 4）,检出限（LOD）为0.01~0.16 ng/L,定量限（LOQ）为0.02~0.52 ng/L,加标回收率为94.3%~102%,相对标准偏差（RSD）为0.49%~10.1%。该法采用10 mL大体积进样,前处理简单、快速且重现性好,可有效实现污水厂尾水中6种酸性药物的定量分析。     

Impairment due to alcohol,tetrahydrocannabinol, and benzodiazepines in impaired drivers compared to experimental studies

Objective: In some countries, per se laws for other drugs than alcohol are used to judge drunk and drugged drivers. These blood concentration limits are often derived from experimental studies on traffic relevant behavior of healthy volunteers. Knowledge about how results from experimental studies could be transferred to a real-life setting is missing. The aim of this study was to compare impairment seen in experimental studies to the impairment seen at equivalent concentrations in apprehended drunk and drugged drivers.

Methods: Results from previously performed meta-analyses of experimental studies regarding impairment from alcohol, tetrahydrocannabinol (THC), and benzodiazepines were compared to impairment in apprehended drunk and drugged drivers as judged by a clinical test of impairment. Both experimental studies and real-life cases were divided into 4 groups according to increasing blood drug concentration intervals. The percentage of impaired test results in experimental studies was compared to the percentage of impaired subjects among drivers within the same blood drug concentration window.

Results: For ethanol, the percentage of impaired drivers (n = 1,223) increased from 59% in the lowest drug concentration group to 95% in the highest drug concentration group, compared to 7 and 72% in the respective groups in experimental studies. For THC, the percentage of impaired drivers (n = 950) increased from 42 to 58%, the corresponding numbers being 11 and 42% for experimental studies. For benzodiazepines, the percentage of impaired drivers (n = 245) increased from 46 to 76%, the corresponding numbers being 16 and 60% for experimental studies. The increased odds ratio for impairment between 2 concentration groups was comparable for experimental studies and impaired drivers.

Conclusions: Fewer test results indicated impairment in experimental studies compared to impaired drivers in real life when influenced by similar blood concentrations of either ethanol, THC, or benzodiazepines. In addition, a comparable relationship between drug concentration and impairment was seen for both experimental studies and real-life cases.

We believe that the present study strengthens the background for using experimental studies to establish fixed concentration limits for drunk and drugged drivers, but experimental studies in an impaired driver population could further expand our knowledge.