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Toxic effects of AB-CHMINACA on liver and kidney and detection of its blood level in adult male mice. AB-CHMINACA 对成年雄性小鼠肝脏和肾脏的毒性作用及其血药浓度检测。
IF 2.8 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-08-13 DOI: 10.1007/s11419-023-00670-0
Soheir Ali Mohammad, Rasha Elhaddad Ali Mousa, Sahar Mohamed Gebril, Khaled Masoud Mohamed Masoud, Rania Ahmad Radwan

Background: AB-CHMINACA is a cannabimimetic indazole derivative. In 2013, it was reported in different countries as a substance of abuse.

Purpose: This study evaluated the subacute toxic effects of AB-CHMINACA on the liver and kidneys and measured its blood level in adult male mice.

Methods: The histological and biochemical subacute toxic effects on the liver and kidneys were assessed after four weeks of daily intraperitoneal injections of one of the following doses: 0.3 mg/kg, 3 mg/kg, or 10 mg/kg as the highest dose in adult male albino mice. In addition, the blood concentration level of AB-CHMINACA was determined by GC-MS-MS.

Results: The histological effects showed congestion, hemorrhage, degeneration, and cellular infiltration of the liver and kidney tissues. Considering the control groups as a reference, biochemical results indicated a significant increase in the serum AST only in the highest dose group, while the ALT and creatinine levels did not significantly change. The mean values of AB-CHMINACA blood levels were 3.05 ± 1.16, 15.08 ± 4.30, and 54.43 ± 8.70 ng/mL for the three treated groups, respectively, one hour after the last dose of intraperitoneal injection. The calibration curves were linear in the 2.5-500 ng/mL concentration range. The intra-assay precision and accuracy of the method were less than 7.0% (RSD) and ± 9.2% (Bias).

Conclusion: This research supports the available case reports on AB-CHMINACA toxicity that it has low lethality; still, the chronic administration causes evident liver and kidney histotoxic effects even at low doses with unnoticeable clinical effects in mice.

背景:AB-CHMINACA是一种大麻拟物吲唑衍生物。目的:本研究评估了 AB-CHMINACA 对成年雄性小鼠肝脏和肾脏的亚急性毒性作用,并测量了其血药浓度:方法:每天腹腔注射以下剂量之一,为期四周,评估其对肝脏和肾脏的组织学和生化亚急性毒性影响:成年雄性白化小鼠的最高剂量为 0.3 毫克/千克、3 毫克/千克或 10 毫克/千克。此外,还通过气相色谱-质谱-质谱法测定了 AB-CHMINACA 的血药浓度水平:结果:组织学效应显示肝脏和肾脏组织充血、出血、变性和细胞浸润。以对照组为参照,生化结果表明,只有最高剂量组的血清谷丙转氨酶(AST)显著升高,而谷草转氨酶(ALT)和肌酐水平没有明显变化。腹腔注射最后一剂 AB-CHMINACA 1 小时后,三个治疗组的血药浓度平均值分别为 3.05 ± 1.16、15.08 ± 4.30 和 54.43 ± 8.70 纳克/毫升。校准曲线在 2.5-500 纳克/毫升浓度范围内呈线性关系。该方法的测定内精密度和准确度分别小于 7.0%(RSD)和 ± 9.2%(偏差):这项研究支持现有的 AB-CHMINACA 毒性病例报告,即它的致死率较低;但长期给药即使剂量较低,也会对小鼠的肝脏和肾脏造成明显的组织毒性影响,且临床影响不明显。
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引用次数: 0
Identification of 1-(thiophene-2-carbonyl)-LSD from blotter paper falsely labeled "1D-LSD". 从误标为 "1D-LSD "的印迹纸中鉴定出 1-(噻吩-2-羰基)-LSD。
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-07-08 DOI: 10.1007/s11419-023-00668-8
Yuki Okada, Kazuki Ueno, Noriko Nishiwaki, Toshihiko Nishimura, Hiroki Segawa, Tadashi Yamamuro, Kenji Kuwayama, Kenji Tsujikawa, Tatsuyuki Kanamori, Yuko T Iwata

Purpose: Since the mid-2010s, lysergic acid diethylamide (LSD) analogs made for substance abuse have periodically emerged. In this case, three pieces of blotter paper labeled "1D-LSD" and presumably impregnated with this LSD analog, were seized. Several websites indicate that 1D-LSD is 1-(1,2-dimethylcyclobutane-1-carbonyl)-LSD. Because this analog is much more difficult to synthesize than previously reported LSD analogs, we doubted that the blotter paper contained 1D-LSD. Herein, we determined the structure of the absorbed compound.

Methods: One of the seized specimens was extracted and analyzed using gas chromatography/mass spectrometry (GC/MS), liquid chromatography/mass spectrometry (LC/MS), high-resolution mass spectrometry (HRMS), and nuclear magnetic resonance (NMR) spectroscopy to estimate the extract components. The estimated compound was then synthesized, yielding an authentic standard. The contents of the seized specimens were identified using authentic standard analysis with GC/MS, LC/MS, and NMR spectroscopy.

Results: Instrumental analyses confirmed the active compound to be 1-(thiophene-2-carbonyl)-LSD, which was inconsistent with the labeling on drug-infused blotter paper.

Conclusion: As in this case, similar blotter paper analyses should consider the possibility of a mismatch between the label and ingredient. To the authors' knowledge, this is the first case report in which 1-(thiophene-2-carbonyl)-LSD was seized and the first seizure of an LSD analog in which an aromatic carboxylic acid had been condensed to LSD. This type of lysergamide may become prevalent in the near future, and we should remain alert for newly appearing lysergamides.

目的:自 2010 年代中期以来,不时出现为滥用药物而制造的麦角酰二乙胺(LSD)类似物。在本案中,查获了三张标有 "1D-LSD "字样的吸墨纸,推测其中浸渍了这种迷幻剂类似物。一些网站指出,1D-LSD 是 1-(1,2-二甲基环丁烷-1-羰基)-LSD。由于这种类似物比之前报道的 LSD 类似物更难合成,我们怀疑印迹纸中含有 1D-LSD。在此,我们确定了所吸收化合物的结构:方法:我们提取了其中一份查获的样本,并使用气相色谱/质谱(GC/MS)、液相色谱/质谱(LC/MS)、高分辨质谱(HRMS)和核磁共振(NMR)光谱进行分析,以估算提取物的成分。然后对估算出的化合物进行合成,得到了真实的标准物质。利用气相色谱/质谱、液相色谱/质谱和核磁共振光谱的真品标准分析鉴定了缴获样品的成分:结果:仪器分析确认活性化合物为 1-(噻吩-2-羰基)-LSD,这与毒品吸墨纸上的标签不一致:结论:与本案例一样,类似的吸墨纸分析应考虑标签与成分不匹配的可能性。据作者所知,这是首次缉获 1-(噻吩-2-羰基)-LSD 的案例报告,也是首次缉获芳香族羧酸与 LSD 缩合的 LSD 类似物。在不久的将来,这种类型的麦角酰氨可能会变得很普遍,我们应该对新出现的麦角酰氨保持警惕。
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引用次数: 0
Cannabigerol (CBG) signal enhancement in its analysis by gas chromatography coupled with tandem mass spectrometry. 气相色谱-串联质谱联用分析中的大麻酚(CBG)信号增强。
IF 2.8 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-09-27 DOI: 10.1007/s11419-023-00673-x
Andrzej L Dawidowicz, Rafal Typek, Michal P Dybowski, Piotr Holowinski, Michal Rombel

Purpose: According to recent reports, cannabigerol (CBG) concentration level in blood and body fluids may have forensic utility as a highly specific albeit insensitive biomarker of recent cannabis smoking. While the analytical sensitivity of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabichromene (CBC) or cannabinol (CBN) estimation by gas chromatography-mass spectrometry (GC-MS) is similar and sufficiently high, it is exceptionally low in the case of CBG (ca. 25 times lower than for the other mentioned cannabinoids). The purpose of this study is to explain the reasons for the extremely low analytical sensitivity of GC-MS in estimating CBG and to present possible ways of its improvement.

Methods: Nuclear magnetic resonance (NMR) data and GC-MS responses to CBG and its various derivatization and transformation products were studied.

Results: The validation data of individual derivatives of CBG and its transformation products were established. CBG silylation/acylation or hydration allows to decrease LOD about 3 times, whereas the formation of pyranic CBG derivative leads to 10-times decrease of LOD. The paper enriches the literature of the subject by providing MS and NMR spectra, not published so far, for derivatives of CBG and its transformation products. The most likely cause of low GC-MS response to CBG is also presented.

Conclusions: The presented results shows that although the signal increase of CBG can be obtained through its derivatization by silylation and/or acylation, the greatest increase is observed in the case of its cyclization to the pyranic CBG form during the sample preparation process. The CBG cyclization procedure is very simple and workable in estimating this cannabinoid in blood/plasma samples.

目的:根据最近的报告,血液和体液中大麻酚(CBG)的浓度水平可能作为近期大麻吸烟的一种高度特异但不敏感的生物标志物具有法医学实用性。虽然通过气相色谱-质谱法(GC-MS)估计的大麻素二醇(CBD)、Δ9-四氢大麻酚(Δ9-THC)、大麻素色烯(CBC)或大麻素(CBN)的分析灵敏度相似且足够高,但在CBG的情况下,其灵敏度异常低(约为其他提到的大麻物质的25倍)。本研究的目的是解释GC-MS在估计CBG时分析灵敏度极低的原因,并提出可能的改进方法。方法:研究了CBG及其各种衍生和转化产物的核磁共振(NMR)数据和GC-MS响应。结果:建立了CBG的单个衍生物及其转化产物的验证数据。CBG甲硅烷基化/酰化或水合可以使LOD降低约3倍,而吡喃CBG衍生物的形成导致LOD降低10倍。该论文提供了CBG衍生物及其转化产物的质谱和核磁共振谱,丰富了该主题的文献。还介绍了GC-MS对CBG反应低的最可能原因。结论:所提出的结果表明,尽管CBG的信号增加可以通过其通过甲硅烷基化和/或酰化的衍生来获得,但在样品制备过程中,观察到其环化为吡喃CBG形式的情况下信号增加最大。CBG环化程序在估计血液/血浆样品中的这种大麻素方面非常简单和可行。
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引用次数: 0
Simultaneous determination of water-soluble herbicides using hydrophilic interaction liquid chromatography-mass spectrometry. 利用亲水作用液相色谱-质谱法同时测定水溶性除草剂。
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-07-22 DOI: 10.1007/s11419-023-00669-7
Daisuke Watanabe, Shuhei Sonoda, Hikoto Ohta

Purpose: The analysis of water-soluble herbicides, including glyphosate (Glyp), glufosinate (Gluf), paraquat (PQ), and diquat (DQ), is time-consuming and expensive because they cannot be analyzed using general toxicological screening methods. Thus, this study aimed to develop a simple and rapid method to simultaneously analyze these compounds without any derivatization nor ion-pairing reagents.

Methods: The analytes were separated using hydrophilic interaction liquid chromatography and detected using tandem mass spectrometry. The developed method was applied to plant and biological samples assuming criminal damage and poisoning cases, respectively.

Results: All analytes were separated well and detected with good peak shapes. For plant samples, the herbicides were specifically detected from withered leaves using a simple extraction method. For biological samples, quantitative analysis was successfully validated, and the limit of quantification values of Glyp and Gluf were 0.2 µg/mL, and those of PQ and DQ were 1 ng/mL.

Conclusion: The developed method had sufficient performance for practical forensic applications including poisoning cases and malicious uses to damage commercial crops.

目的:分析水溶性除草剂,包括草甘膦(Glyp)、草铵膦(Gluf)、百草枯(PQ)和敌草快(DQ),既费时又费钱,因为它们不能用一般的毒理学筛选方法进行分析。因此,本研究旨在开发一种简单快速的方法,在不使用任何衍生或离子配对试剂的情况下同时分析这些化合物:方法:使用亲水相互作用液相色谱法分离分析物,并使用串联质谱法进行检测。结果:所有分析物均能很好地分离并检测到:结果:所有分析物均分离良好,检测峰形良好。在植物样品中,采用简单的提取方法就能从枯叶中检测到除草剂。对生物样品进行了定量分析,Glyp 和 Gluf 的定量限为 0.2 µg/mL,PQ 和 DQ 的定量限为 1 ng/mL:结论:所开发的方法具有良好的性能,可用于实际的法医应用,包括中毒案件和恶意使用农药破坏经济作物的案件。
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引用次数: 0
Death after smoking of fentanyl, 5F-ADB, 5F-MDMB-P7AICA and other synthetic cannabinoids with a bucket bong. 用水桶烟斗吸食芬太尼、5F-ADB、5F-MDMB-P7AICA 和其他合成大麻素后死亡。
IF 2.8 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-06-10 DOI: 10.1007/s11419-023-00666-w
Merja A Neukamm, Sebastian Halter, Volker Auwärter, Georg Schmitt, Arianna Giorgetti, Marc Bartel

Purpose: We report a case of a polydrug user who consumed various synthetic cannabinoids and fentanyl from a transdermal patch via a bucket bong. Toxicological results from postmortem matrices with special focus on synthetic cannabinoids are discussed in terms of their relevance to the death.

Methods: The samples were analyzed by toxicological screening procedures involving immunoassays and gas chromatography-mass spectrometry (GC-MS) as well as quantitative analyses by means of GC-MS and high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: At the autopsy, coronary artery disease and signs of liver congestion were noted, in the absence of acute myocardial ischemic changes. Femoral blood concentrations of fentanyl and pregabalin were 14 ng/mL and 3,200 ng/mL, respectively. In addition, 2.7 ng/mL 5F-ADB and 13 ng/mL 5F-MDMB-P7AICA were detected together with relatively low amounts of 5 other synthetic cannabinoids in cardiac blood. A total number of up to 17 synthetic cannabinoids were detected in kidney, liver, urine and hair. Fentanyl and 5F-ADB were also detected in the water of the bucket bong.

Conclusions: The cause of death could be attributed to an acute mixed intoxication by fentanyl and 5F-ADB (both Toxicological Significance Score (TSS) = 3) with a contribution of pregabalin and 5F-MDMB-P7AICA (TSS = 2), in a subject suffering from pre-existing heart damage. The most plausible mechanism of death consists in a respiratory depression. This case report demonstrates that use of opioids in combination with synthetic cannabinoids might be particularly dangerous.

目的:我们报告了一例使用多种药物的患者,他通过水桶水烟袋从透皮贴片中吸食了多种合成大麻素和芬太尼。我们讨论了尸检基质的毒理学结果,重点是合成大麻素与死亡的相关性:方法:通过免疫测定和气相色谱-质谱法(GC-MS)等毒理学筛选程序以及气相色谱-质谱法和高效液相色谱-串联质谱法(LC-MS/MS)进行定量分析:尸检结果:在没有急性心肌缺血病变的情况下,发现了冠状动脉疾病和肝脏充血的迹象。股动脉血中芬太尼和普瑞巴林的浓度分别为 14 纳克/毫升和 3,200 纳克/毫升。此外,在心肌血液中还检测到 2.7 纳克/毫升的 5F-ADB 和 13 纳克/毫升的 5F-MDMB-P7AICA 以及其他 5 种含量相对较低的合成大麻素。在肾脏、肝脏、尿液和毛发中总共检测到多达 17 种合成大麻素。在水桶烟斗的水中还检测到芬太尼和 5F-ADB :死因可归咎于芬太尼和 5F-ADB 的急性混合中毒(毒理学意义评分均为 3 分),以及普瑞巴林和 5F-MDMB-P7AICA 的中毒(毒理学意义评分为 2 分)。最合理的死亡机制是呼吸抑制。该病例报告表明,阿片类药物与合成大麻素合用可能特别危险。
{"title":"Death after smoking of fentanyl, 5F-ADB, 5F-MDMB-P7AICA and other synthetic cannabinoids with a bucket bong.","authors":"Merja A Neukamm, Sebastian Halter, Volker Auwärter, Georg Schmitt, Arianna Giorgetti, Marc Bartel","doi":"10.1007/s11419-023-00666-w","DOIUrl":"10.1007/s11419-023-00666-w","url":null,"abstract":"<p><strong>Purpose: </strong>We report a case of a polydrug user who consumed various synthetic cannabinoids and fentanyl from a transdermal patch via a bucket bong. Toxicological results from postmortem matrices with special focus on synthetic cannabinoids are discussed in terms of their relevance to the death.</p><p><strong>Methods: </strong>The samples were analyzed by toxicological screening procedures involving immunoassays and gas chromatography-mass spectrometry (GC-MS) as well as quantitative analyses by means of GC-MS and high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).</p><p><strong>Results: </strong>At the autopsy, coronary artery disease and signs of liver congestion were noted, in the absence of acute myocardial ischemic changes. Femoral blood concentrations of fentanyl and pregabalin were 14 ng/mL and 3,200 ng/mL, respectively. In addition, 2.7 ng/mL 5F-ADB and 13 ng/mL 5F-MDMB-P7AICA were detected together with relatively low amounts of 5 other synthetic cannabinoids in cardiac blood. A total number of up to 17 synthetic cannabinoids were detected in kidney, liver, urine and hair. Fentanyl and 5F-ADB were also detected in the water of the bucket bong.</p><p><strong>Conclusions: </strong>The cause of death could be attributed to an acute mixed intoxication by fentanyl and 5F-ADB (both Toxicological Significance Score (TSS) = 3) with a contribution of pregabalin and 5F-MDMB-P7AICA (TSS = 2), in a subject suffering from pre-existing heart damage. The most plausible mechanism of death consists in a respiratory depression. This case report demonstrates that use of opioids in combination with synthetic cannabinoids might be particularly dangerous.</p>","PeriodicalId":12329,"journal":{"name":"Forensic Toxicology","volume":" ","pages":"82-92"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10808286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9655355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identifying a suspect powder as a cannabis concentrate through chemical analysis and DNA testing. 通过化学分析和 DNA 检测确定可疑粉末为浓缩大麻。
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-08-21 DOI: 10.1007/s11419-023-00672-y
Tadashi Yamamuro, Yusuke Saito, Yuki Okada, Hiroki Segawa, Kenji Kuwayama, Kenji Tsujikawa, Tatsuyuki Kanamori, Yuko T Iwata

Purpose: Cannabis is regulated in many countries, and cannabis products are diversifying, which can hinder identification. Here, we report the seizure of a powder sample with a cannabis-like odor in a spice bottle labeled "nutmeg" and identification of the sample by chemical testing and cannabis DNA testing.

Methods: The sample was observed under a microscope, extracted with methanol, and analyzed by gas chromatography-mass spectrometry (GC-MS). The chemical profile of the seized powder was compared with that of nutmeg samples. Gas chromatography-flame ionization detection was used to estimate the total Δ9-tetrahydrocannabinol (Δ9-THC) concentration in the sample. A commercially available cannabis DNA testing kit was used to confirm the presence of cannabis plant DNA in the seized sample.

Results: The characteristics of cannabis in the seized powder were difficult to determine through microscopic observation alone. GC-MS analysis identified β-caryophyllene (an aromatic component of cannabis) and five cannabinoids unique to cannabis, including Δ9-THC. No common compounds were identified in the seized powder or nutmeg samples. The total Δ9-THC concentration in the sample was very high (approximately 47% by weight). Cannabis DNA testing confirmed that the seized powder contained cannabis.

Conclusions: The seized powder was found to be a processed product made from a finely pulverized resin-like cannabis concentrate. Our results indicate that combined chemical and DNA analysis should help identify cannabis-related samples in various forms.

目的:许多国家都对大麻进行管制,大麻产品也日趋多样化,这可能会妨碍识别工作。在此,我们报告了在一个标有 "肉豆蔻 "的香料瓶中查获的具有类似大麻气味的粉末样本,以及通过化学测试和大麻 DNA 测试对样本进行鉴定的情况:方法:在显微镜下观察样品,用甲醇提取,并用气相色谱-质谱法(GC-MS)进行分析。将缉获的粉末与肉豆蔻样品的化学成分进行比较。气相色谱-火焰离子化检测法用于估算样品中的Δ9-四氢大麻酚(Δ9-THC)总浓度。使用市售的大麻 DNA 检测试剂盒确认缉获样本中是否含有大麻植物 DNA:结果:仅通过显微镜观察很难确定所缉获粉末中大麻的特征。气相色谱-质谱分析确定了 β-石竹烯(大麻的一种芳香成分)和五种大麻特有的大麻素,包括 Δ9-四氢大麻酚。在缉获的粉末或肉豆蔻样品中没有发现常见的化合物。样品中的Δ9-THC 总浓度非常高(按重量计约为 47%)。大麻 DNA 检测证实缉获的粉末中含有大麻:发现缉获的粉末是一种由树脂状大麻浓缩物精细粉碎而成的加工产品。我们的结果表明,结合化学和 DNA 分析应有助于鉴别各种形式的大麻相关样本。
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引用次数: 0
Alcohol spiked with zolpidem and midazolam potentiates inflammation, oxidative stress and organ damage in a mouse model. 在小鼠模型中,掺入唑吡坦和咪唑安定的酒精会增强炎症、氧化应激和器官损伤。
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2024-01-01 Epub Date: 2023-10-09 DOI: 10.1007/s11419-023-00674-w
Biwott Kipchumba, Francis Gitonga, Careen Jepchirchir, Grace Wairimu Gitau, Patrick W Okanya, Peris Wanza Amwayi, Alfred Orina Isaac, Nyariki James Nyabuga

Purpose: Crime-related spiking of alcoholic drinks with prescription drugs is quite common and has been happening for centuries. This study, therefore, evaluated the effects of oral administration of alcohol spiked with the zolpidem and midazolam potent sedatives on inflammation, oxidative stress and various organ damage in male Swiss albino mice.

Methods: Mice were randomly assigned into six treatment groups; the first group constituted the normal control, the second group received 50 mg/kg body weight of zolpidem only, the third group received 50 mg/kg body weight zolpidem dissolved in 5 g/kg alcohol, the fourth group received 50 mg/kg midazolam only, the fifth group received midazolam (50 mg/kg) dissolved in 5 g/kg alcohol and the sixth group received 5 g/kg alcohol.

Results: Alcohol-induced significant reduction in neurological function and altered blood hematological indicators. Such neurological impairment and negative effects on blood were exacerbated in mice administered with spiked alcohol. Additionally, midazolam and zolpidem enhanced alcohol-driven elevation of liver function markers; the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) gamma glutamyltransferase (GGT), total bilirubin and alkaline phosphatase. Exposure to alcohol and/or spiked alcohol led to significant augmentation of nitric oxide and malonaldehyde, with concomitant depletion of liver glutathione (GSH) levels. Similarly, serum levels of pro-inflammatory cytokines tumor necrosis factor alpha and interferon-gamma were increased by co-exposure with midazolam or zolpidem. Alcohol-induced hepatotoxicity and nephrotoxicity were amplified by exposure to alcohol spiked with midazolam/zolpidem.

Conclusion: Exposure to alcohol spiked with midazolam or zolpidem appears to exacerbate neurological deficits, inflammation, oxidative stress, and organ damage.

目的:在酒精饮料中添加处方药的犯罪行为很常见,而且已经发生了几个世纪。因此,本研究评估了口服掺有唑吡坦和咪达唑仑强效镇静剂的酒精对雄性瑞士白化病小鼠炎症、氧化应激和各种器官损伤的影响。方法:将小鼠随机分为6个治疗组;第一组为正常对照组,第二组仅接受50mg/kg体重的唑吡坦,第三组接受50mg/kg重量的溶于5g/kg酒精的唑吡丹,第四组仅接受20mg/kg咪达唑仑,第五组接受50mmg/kg溶于5gg/kg酒精的咪达唑安定,第六组接受5g/kg酒精。结果:酒精导致神经功能显著下降,血液学指标改变。在服用掺入酒精的小鼠中,这种神经损伤和对血液的负面影响加剧了。此外,咪达唑仑和唑吡坦增强了酒精驱动的肝功能标志物的升高;血清天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、γ-谷氨酰转移酶(GGT)、总胆红素和碱性磷酸酶。暴露于酒精和/或掺入酒精导致一氧化氮和丙二醛显著增加,同时肝脏谷胱甘肽(GSH)水平降低。同样,与咪达唑仑或唑吡坦共同暴露可增加血清促炎细胞因子肿瘤坏死因子α和干扰素γ的水平。酒精诱导的肝毒性和肾毒性通过暴露于掺有咪唑安定/唑吡坦的酒精而加剧。结论:暴露于掺入咪唑安定或唑吡坦酒精似乎会加剧神经缺陷、炎症、氧化应激和器官损伤。
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引用次数: 0
Determination of 3- and 4-chloromethcathinone interactions with plasma proteins: study involving analytical and theoretical methods 测定 3-和 4-氯甲卡西酮与血浆蛋白的相互作用:涉及分析和理论方法的研究
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2023-12-18 DOI: 10.1007/s11419-023-00677-7
Piotr Holowinski, Michal P. Dybowski

Purpose

The purpose of this paper was to determine 3- and 4-chloromethcathinone (3- and 4-CMC) binding degree and possible binding interaction modes with human serum albumin (HSA) using analytical and theoretical methods.

Methods

Experimental determination of 3- and 4-CMC binding degree with HSA was performed using gas chromatography–tandem mass spectrometry preceded by the equilibrium dialysis (ED) and ultrafiltration (UF). Nuclear magnetic resonance (NMR) spectroscopy was used to determine 3- and 4-CMC epitope-binding maps and possible binding sites in HSA. The molecular docking and molecular dynamics were employed to obtain detailed information about binding modes of 3- and 4-CMC enantiomers in HSA.

Results

As follows from the presented data, the degree of binding of 3- and 4-CMC is at a similar level of approx. 80%. This indicates a relatively strong binding of CMC to plasma proteins. The model studies employing the NMR spectroscopy and molecular simulations indicate that both CMCs bind to HSA. The whole 3- and 4-CMC molecules are embedded in the binding sites, with aromatic moieties being in the closest contact with the HSA residues. Moreover, conducted experiments show that Sudlow site II is the main binding center for 3- and 4-CMC and Sudlow site I acts as the secondary binding site.

Conclusions

Although many studies describe pharmacological and toxicological properties of synthetic cathinones (SC), the data taking SCs binding in plasma into consideration are scarce. To our knowledge, this is the first report presenting comprehensive experimental and theoretical characterization of 3- and 4-CMC binding with plasma proteins.

方法在平衡透析(ED)和超滤(UF)之前,采用气相色谱-串联质谱法实验测定 3-和 4-氯甲卡西酮(3-和 4-CMC)与人血清白蛋白(HSA)的结合程度和可能的结合相互作用模式。核磁共振(NMR)光谱用于确定 3-CMC 和 4-CMC 表位结合图和 HSA 中可能的结合位点。通过分子对接和分子动力学研究,获得了 3-CMC 和 4-CMC 对映异构体在 HSA 中结合模式的详细信息。这表明 CMC 与血浆蛋白的结合力相对较强。利用核磁共振光谱和分子模拟进行的模型研究表明,两种 CMC 都能与 HSA 结合。整个 3-CMC 和 4-CMC 分子都嵌入了结合位点,其中芳香分子与 HSA 残基的接触最为密切。此外,实验还表明,Sudlow 位点 II 是 3-CMC 和 4-CMC 的主要结合中心,而 Sudlow 位点 I 则是次要结合位点。据我们所知,这是第一份全面介绍 3-CMC 和 4-CMC 与血浆蛋白结合的实验和理论特征的报告。
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引用次数: 0
Acute and subacute toxic effects of CUMYL-4CN-BINACA on male albino rats CUMYL-4CN-BINACA 对雄性白化大鼠的急性和亚急性毒性作用
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2023-12-15 DOI: 10.1007/s11419-023-00676-8
Ayşe Lafzi, Fatma Yeşilyurt, Tuba Demirci, Ahmet Hacımüftüoğlu, Turgay Şişman

Purpose

There is very little information about the toxicological and pathological effects of synthetic cannabinoids, which have cannabis-like properties. This study was carried out to histopathologically, hematologically, and biochemically determine the toxic effects of acute and subacute exposure to a novel synthetic cannabinoid 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide in internal organs of adult male rats.

Methods

The cannabinoid was injected intraperitoneally at three doses (0.5, 1.0, and 2.0 mg/kg, body weight). The cannabinoid was administered to acute groups for 2 days and to subacute groups for 14 days. Observations were made for 14 days and various changes such as mortality, injury, and illness were recorded daily. Hematological and biochemical changes were evaluated and histopathological analyses in lung, liver, and kidney tissues were also performed.

Results

No mortality was observed. It was observed that there were fluctuations in hematological and serum biochemical parameters. Among the oxidative stress parameters, significant decreases in superoxide dismutase, catalase levels and significant increases in lipid peroxidation levels were determined. Serious pathological changes such as necrosis, vacuolation, congestion, and fibrosis were observed in the internal organs in a dose-dependent and time-dependent manner. It was also found that the synthetic cannabinoid triggered apoptosis in the organs. The results demonstrated that the most affected organ by the cannabinoid was the kidney.

Conclusion

This study showed for the first time that CUMYL-4CN-BINACA adversely affects healthy male albino rats. It can be estimated that the abuse of the cannabinoid may harm human health in the same way.

目的关于具有类似大麻特性的合成大麻素的毒理学和病理学影响的信息很少。本研究旨在从组织病理学、血液学和生物化学角度确定急性和亚急性接触新型合成大麻素 1-(4-氰基丁基)-N-(2-苯基丙-2-基)吲唑-3-甲酰胺对成年雄性大鼠内脏器官的毒性影响。给急性组大鼠注射大麻素 2 天,给亚急性组大鼠注射大麻素 14 天。观察 14 天,每天记录死亡率、受伤和疾病等各种变化。对血液学和生化变化进行了评估,并对肺、肝和肾组织进行了组织病理学分析。观察发现,血液和血清生化指标有波动。在氧化应激参数中,超氧化物歧化酶和过氧化氢酶水平显著下降,脂质过氧化水平显著上升。在内脏器官中观察到了严重的病理变化,如坏死、空泡化、充血和纤维化,这些变化具有剂量依赖性和时间依赖性。研究还发现,合成大麻素会引发器官凋亡。结果表明,受大麻素影响最大的器官是肾脏。可以估计,滥用大麻素可能会以同样的方式危害人类健康。
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引用次数: 0
Identification of LSD analogs, 1cP-AL-LAD, 1cP-MIPLA, 1V-LSD and LSZ in sheet products. 鉴定片状产品中的 LSD 类似物、1cP-AL-LAD、1cP-MIPLA、1V-LSD 和 LSZ。
IF 2.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2023-07-01 Epub Date: 2023-02-21 DOI: 10.1007/s11419-023-00661-1
Rie Tanaka, Maiko Kawamura, Sakumi Mizutani, Ruri Kikura-Hanajiri

Purpose: Many analogs of lysergic acid diethylamide (LSD) have recently appeared as designer drugs around the world. These compounds are mainly distributed as sheet products. In this study, we identified three more newly distributed LSD analogs from paper sheet products.

Methods: The structures of the compounds were determined by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS), liquid chromatography with hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy.

Results: From the NMR analysis, the compounds in the four products were identified as 4-(cyclopropanecarbonyl)-N,N-diethyl-7-(prop-2-en-1-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1cP-AL-LAD), 4-(cyclopropanecarbonyl)-N-methyl-N-isopropyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (1cP-MIPLA), N,N-diethyl-7-methyl-4-pentanoyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1V-LSD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ). In comparison with the structure of LSD, 1cP-AL-LAD was converted at the positions at N1 and N6, and 1cP-MIPLA was converted at the positions at N1 and N18. The metabolic pathways and biological activities of 1cP-AL-LAD and 1cP-MIPLA have not been reported.

Conclusions: This is the first report showing that LSD analogs that were converted at multiple positions have been detected in sheet products in Japan. There are concerns about the future distribution of sheet drug products containing new LSD analogs. Therefore, the continuous monitoring for newly detected compounds in sheet products is important.

目的:麦角酰二乙胺(LSD)的许多类似物最近作为特制毒品出现在世界各地。这些化合物主要以片状产品的形式销售。在这项研究中,我们又从纸片产品中鉴定出了三种新的麦角酰二乙胺类似物:方法:采用气相色谱-质谱联用仪(GC-MS)、液相色谱-光电二极管阵列质谱联用仪(LC-PDA-MS)、液相色谱-混合四极杆飞行时间质谱联用仪(LC-Q-TOF-MS)和核磁共振(NMR)光谱测定了这些化合物的结构:6,6a,7,8,9-六氢吲哚并[4,3-fg]喹啉-9-甲酰胺(1cP-MIPLA)、N,N-二乙基-7-甲基-4-戊酰基-4,6,6a,7,8,9-六氢吲哚并[4,3-fg]喹啉-9-甲酰胺(1V-LSD)和(2'S,4'S)-麦角酸 2,4-二甲基氮杂环丁烷(LSZ)。与 LSD 的结构相比,1cP-AL-LAD 在 N1 和 N6 的位置上发生了转化,1cP-MIPLA 在 N1 和 N18 的位置上发生了转化。1cP-AL-LAD 和 1cP-MIPLA 的代谢途径和生物活性尚未见报道:这是首次有报告显示,在日本的片状产品中发现了在多个位置被转化的 LSD 类似物。人们对含有新型 LSD 类似物的片剂药物产品的未来销售表示担忧。因此,持续监测片剂产品中新检测出的化合物非常重要。
{"title":"Identification of LSD analogs, 1cP-AL-LAD, 1cP-MIPLA, 1V-LSD and LSZ in sheet products.","authors":"Rie Tanaka, Maiko Kawamura, Sakumi Mizutani, Ruri Kikura-Hanajiri","doi":"10.1007/s11419-023-00661-1","DOIUrl":"10.1007/s11419-023-00661-1","url":null,"abstract":"<p><strong>Purpose: </strong>Many analogs of lysergic acid diethylamide (LSD) have recently appeared as designer drugs around the world. These compounds are mainly distributed as sheet products. In this study, we identified three more newly distributed LSD analogs from paper sheet products.</p><p><strong>Methods: </strong>The structures of the compounds were determined by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS), liquid chromatography with hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy.</p><p><strong>Results: </strong>From the NMR analysis, the compounds in the four products were identified as 4-(cyclopropanecarbonyl)-N,N-diethyl-7-(prop-2-en-1-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1cP-AL-LAD), 4-(cyclopropanecarbonyl)-N-methyl-N-isopropyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (1cP-MIPLA), N,N-diethyl-7-methyl-4-pentanoyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1V-LSD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ). In comparison with the structure of LSD, 1cP-AL-LAD was converted at the positions at N1 and N6, and 1cP-MIPLA was converted at the positions at N1 and N18. The metabolic pathways and biological activities of 1cP-AL-LAD and 1cP-MIPLA have not been reported.</p><p><strong>Conclusions: </strong>This is the first report showing that LSD analogs that were converted at multiple positions have been detected in sheet products in Japan. There are concerns about the future distribution of sheet drug products containing new LSD analogs. Therefore, the continuous monitoring for newly detected compounds in sheet products is important.</p>","PeriodicalId":12329,"journal":{"name":"Forensic Toxicology","volume":"41 2","pages":"294-303"},"PeriodicalIF":2.2,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10310582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10101108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Forensic Toxicology
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