Toxicity of the 3,4-methylenedioxymethamphetamine and its enantiomers to Daphnia magna after isolation by semipreparative chromatography

MDMA (3,4-methylenedioxymethamphetamine) is a chiral psychoactive recreational drug sold in illicit markets as racemate. Studies on the impact of MDMA on aquatic organisms are scarce. While enantioselectivity in toxicity in animals and humans has been reported, none is reported on aquatic organisms. This study aimed to investigate the ecotoxicological effects of MDMA and its enantiomers in Daphnia magna. For that, enantiomers (enantiomeric purity > 97%) were separated by liquid chromatography using a homemade semipreparative chiral column. Daphnids were exposed to three concentrations of (R,S)-MDMA (0.1, 1.0 and 10.0 µg L−1) and two concentrations of (R)- and (S)-enantiomers (0.1 and 1.0 µg L−1) over the course of 8 days. Morphophysiological responses were dependent on the substance form and daphnia development stage, and they were overall not affected by the (R)-enantiomer. Changes in swimming behaviour were observed for both the racemate and its enantiomers, but enantioselective effects were not observed. Reproductive or biochemical changes were not observed for enantiomers whereas a significant decrease in acetylcholinesterase and catalase activity was noted at the highest concentration of (R,S)-MDMA (10 µg L−1). Overall, this study showed that sub-chronic exposure to MDMA racemate and its enantiomers can interfere with morphophysiological and swimming behaviour of D. magna. In general, the (R)-enantiomer demonstrated less toxicity than the (S)-enantiomer.This work was financially supported by national funds through the FCT/MCTES (PIDDAC), under the project PTDC/CTA-AMB/6686/2020, and partially supported through the projects UIDB/04423/2020 and UIDP/04423/2020 (Group of Natural Products and Medicinal ChemistryCIIMAR)

Analysis of psychoactive substances in surface waters

The changes in the law to keep drug trafficking and consumption under control have increased illicit market of psychoactive substances (PAS) and the synthesis and introduction of new psychoactive substances (NPS). On the other hand, many PAS are chiral and available either as racemate or enantiomerically pure and determination of the enantiomeric fraction is essential for a comprehensive analysis of drug consumption and evaluation of environmental risk. These substances reach the environment through different ways such as direct disposal by industry, illegal discharges and manly as humans excretion products (of parent compounds and/or metabolites) through the effluents of wastewater treatment plants (WWTP). Occurrence of PAS in surface waters can give insights about their consumption in a specific region and EF can provide valuable information about synthetic pathways and distinction between direct disposal or consumption. Therefore, the aim of this work was to develop and validate an indirect method by gas chromatography-mass spectrometry (GC-MS) based on the formation of diastereomers using (R)-(-)-α-methoxy-α- (trifluoromethyl) phenylacetyl chloride ((R)-MTPA-Cl) as chiral derivatization reagent, for enantiomeric quantification of eight PAS including three amphetamine like substances namely amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymethamphetamine (MDMA), the metabolite norketamine (NK), and four synthetic cathinones, buphedrone (BPD), butylone (BTL), 3,4-dimethylmethcathinone (3,4-DMMC) and 3-methylmethcathinone (3-MMC). Also, two illicit piperazines (PP) namely 1-benzylpiperazine (1-BP) and 1-(4-metoxyphenyl)-piperazine (1,4-MPP) were included. PP were also derivatized with (R)-MTPA-Cl. The optimized conditions allowed the quantification of the target PAS (a total of 16 diastereomers and two PP derivatives) in less than 24.0 min. The method was validated according to the International Conference on Harmonization (ICH) in terms of selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, intra and inter-precision and recovery. The method showed to be selective and correlation coefficients were higher than 0.98. The LOD ranged from 17 to 100 ng L-1 and LOQ varied between 50 and 300 ng L-1. The method demonstrated to be accurate (82.4 to 116.9%), precise (up to 8.5%) and recoveries ranged from 25 to 105.5%. The method was used to evaluate the occurrence, spatial distribution, and the EF of the target PAS in Portuguese surface waters in the Great Porto region and effluents from two WWTPs. For that, 1 L of surface estuarine water samples were collected at five sampling points along the Douro river estuary. Further, effluents samples were collected from two WWTPs that discharge their treated wastewaters for Douro river tributaries. Of the 18 compounds included in this work, 5 were detected in estuarine water and 6 in WWTPs. Both enantiomers of AMP, and only one enantiomer of MAMP, MDMA and BPD were found in estuarine waters, but below LOQ. Effluents samples showed only one enantiomer of AMP, BPD, 3,4-DMMC, but both enantiomers of MDMA (present though at concentrations below the LOQ). MAMP was also detected in both WWTPs in range of <LOQ - 57.30 ng L-1 with enantiomeric fraction (EF) ≅1. These results showed the occurrence of AMPs and for the first time the presence of illicit synthetic cathinones in Douro river estuary and effluents. Occurrence of MAMP in both surface waters and effluent samples suggests consumption rather than direct disposal. The occurrence of synthetic cathinones, namely BPD was found and reported for the first time in Portuguese surface waters. Analysis of effluent samples also detected for the first time the occurrence of synthetic cathinones (BPD and 3,4-DMMC) and EF suggests enantioselective processes. Further studies are needed considering the elution order of the diastereomers for a comprehensive analysis of the data. Though data from this study was obtained from one sampling period, results show the potential of the method to monitor the target PAS

Gas Chromatography Multiresidue Method for Enantiomeric Fraction Determination of Psychoactive Substances in Effluents and River Surface Waters

Determination of psychoactive substances (PAS) and/or their metabolites in surface waters is crucial for environmental risk assessment, and disclosure of their enantiomeric fractions (EF) allows discrimination between consumption, direct disposal, and synthesis pathways. The aim of this study was to develop and validate an indirect method by gas chromatography coupled to mass spectrometry (GC–MS) based on derivatization using (R)-(−)-α-methoxy-α-(trifluoromethyl) phenylacetyl chloride as chiral derivatization reagent, for enantiomeric quantification of amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymethamphetamine (MDMA), norketamine, buphedrone (BPD), butylone, 3,4-dimethylmethcathinone (3,4-DMMC), 3-methylmethcathinone, and quantification of 1-benzylpiperazine and 1-(4-metoxyphenyl)-piperazine. The method allowed to evaluate the occurrence, spatial distribution, and the EF of the target chiral PAS in Portuguese surface waters and in effluents from 2 wastewater treatment plants (WWTP). For that, water samples were pre-concentrated by solid phase extraction using OASIS® MCX cartridges, derivatized and further analyzed by GC–MS. Both enantiomers of AMP, (R)-MDMA, (S)-MAMP, and the first eluted enantiomer of BPD (configuration not assigned) were found in surface waters, while effluent samples showed both enantiomers of MDMA, (S)-MAMP, (R)-AMP, and the first eluted enantiomer of BPD and 3,4-DMMC. According to our knowledge, this is the first multiresidue analytical method by CG–MS enrolling cathinones, amphetamines, and piperazines. The presence of illicit synthetic cathinones in Douro River estuary is here reported for the first time, along with other amphetamine derivatives. The potential of the method to monitor consumption of the target PAS was demonstrated

Toxicity of the 3,4-Methylenedioxymethamphetamine and Its Enantiomers to Daphnia magna after Isolation by Semipreparative Chromatography

MDMA (3,4-methylenedioxymethamphetamine) is a chiral psychoactive recreational drug sold in illicit markets as racemate. Studies on the impact of MDMA on aquatic organisms are scarce. While enantioselectivity in toxicity in animals and humans has been reported, none is reported on aquatic organisms. This study aimed to investigate the ecotoxicological effects of MDMA and its enantiomers in Daphnia magna. For that, enantiomers (enantiomeric purity &gt; 97%) were separated by liquid chromatography using a homemade semipreparative chiral column. Daphnids were exposed to three concentrations of (R,S)-MDMA (0.1, 1.0 and 10.0 &micro;g L&minus;1) and two concentrations of (R)- and (S)-enantiomers (0.1 and 1.0 &micro;g L&minus;1) over the course of 8 days. Morphophysiological responses were dependent on the substance form and daphnia development stage, and they were overall not affected by the (R)-enantiomer. Changes in swimming behaviour were observed for both the racemate and its enantiomers, but enantioselective effects were not observed. Reproductive or biochemical changes were not observed for enantiomers whereas a significant decrease in acetylcholinesterase and catalase activity was noted at the highest concentration of (R,S)-MDMA (10 &micro;g L&minus;1). Overall, this study showed that sub-chronic exposure to MDMA racemate and its enantiomers can interfere with morphophysiological and swimming behaviour of D. magna. In general, the (R)-enantiomer demonstrated less toxicity than the (S)-enantiomer

Development and validation of a brief dementia screening indicator for primary care

BackgroundDetection of “any cognitive impairment” is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.MethodsWe developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high‐risk patients to target for cognitive screening.ResultsThe final Dementia Screening Indicator included age (1 point/year; ages, 65–79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m2 (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell’s C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).ConclusionsThe Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high‐risk patients to target for cognitive screening.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152503/1/alzjjalz201311006.pd

Vascular Cognitive Impairment: Disease Mechanisms and Therapeutic Implications

The prevalence of vascular cognitive impairment (VCI) is likely to increase as the population ages and cardiovascular disease survival improves. We provide an overview of the definition and disease mechanisms of VCI and present a systematic literature review of the current evidence for the pharmacologic and nonpharmacologic therapies used to treat the VCI symptoms of cognitive dysfunction or to modify VCI through primary and secondary prevention. The Cochrane Database of Systematic Reviews was searched from 2005 to October 2010 using the keywords “vascular dementia” or “vascular cognitive impairment and therapy.” MEDLINE was searched for English-language articles published within the last 10 years using the combined Medical Subject Headings (MeSH) “therapeutics and dementia,” “vascular” or “vascular cognitive impairment.” Although cholinesterase inhibitors and memantine produce small cognitive improvements in patients with VCI, these drugs do not improve global clinical outcomes and have adverse effects and costs. Selective serotonin reuptake inhibitors and dihydropyridine calcium channel blockers may improve short-term cognitive function in patients with VCI. Anti-hypertensive therapy with an ACE inhibitor-based regimen and statins may prevent the major subtype of VCI known as poststroke cognitive decline. Clinical and effectiveness studies with long-term follow-up are needed to determine the benefits and risks of pharmacologic and nonpharmacologic therapies to prevent and treat VCI. Given its growing health, social, and economic burden, the prevention and treatment of VCI are critical priorities for clinical care and research