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1.
J Anal Toxicol ; 44(8): 803-810, 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33313885

RESUMO

Drug degradation as a consequence of putrefactive bacterial activity is a well-known factor that affects the identification and quantitation of certain substances of forensic interest. Current knowledge on putrefaction-mediated degradation of drugs is, however, significantly lacking. This study aimed to investigate the degradation of 4-methylmethcathinone (4-MMC or mephedrone) and to detect its degradation products in putrefied biological matrices containing 4-MMC. The bacteria species Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris were grown in brain-heart infusion broth, spiked with 4-MMC and incubated at 37°C for 24 h. Postmortem human blood and fresh porcine liver macerate were also left to putrefy in sample tubes at room temperature for 1 week. Structural elucidation was based on modern spectroscopic analyses including the use of high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. All four putrefactive bacteria were capable of degrading 4-MMC extensively under the experimental conditions explored. Of particular interest was the discovery of a novel degradation product common to all four bacterial species, which was assigned as 2-hydroxy-1-(4-methylphenyl)propan-1-one (HMP) based on the spectroscopic data. This degradation product was detectable in both postmortem human blood and porcine liver samples. The stability of the identified degradation products, especially HMP, should be further investigated to assess their validity of serving as marker analytes for monitoring 4-MMC in postmortem toxicology.


Assuntos
Drogas Ilícitas/química , Metanfetamina/análogos & derivados , Animais , Biomarcadores , Cromatografia Líquida , Humanos , Fígado , Espectroscopia de Ressonância Magnética , Metanfetamina/química , Mudanças Depois da Morte , Suínos
2.
Nucleic Acids Res ; 48(20): e120, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33053182

RESUMO

In vitro aptamer isolation methods can yield hundreds of potential candidates, but selecting the optimal aptamer for a given application is challenging and laborious. Existing aptamer characterization methods either entail low-throughput analysis with sophisticated instrumentation, or offer the potential for higher throughput at the cost of providing a relatively increased risk of false-positive or -negative results. Here, we describe a novel method for accurately and sensitively evaluating the binding between DNA aptamers and small-molecule ligands in a high-throughput format without any aptamer engineering or labeling requirements. This approach is based on our new finding that ligand binding inhibits aptamer digestion by T5 exonuclease, where the extent of this inhibition correlates closely with the strength of aptamer-ligand binding. Our assay enables accurate and efficient screening of the ligand-binding profiles of individual aptamers, as well as the identification of the best target binders from a batch of aptamer candidates, independent of the ligands in question or the aptamer sequence and structure. We demonstrate the general applicability of this assay with a total of 106 aptamer-ligand pairs and validate these results with a gold-standard method. We expect that our assay can be readily expanded to characterize small-molecule-binding aptamers in an automated, high-throughput fashion.


Assuntos
Aptâmeros de Nucleotídeos/química , Exodesoxirribonucleases/química , Técnica de Seleção de Aptâmeros/métodos , DNA/química , Sequências Repetidas Invertidas , Ligantes , Metanfetamina/análogos & derivados , Metanfetamina/química , Ligação Proteica
3.
Toxicol Lett ; 331: 42-52, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464236

RESUMO

Synthetic cathinones abuse remains a serious public health problem. Kidney injury has been reported in intoxications associated with synthetic cathinones, but the molecular mechanisms involved have not been explored yet. In this study, the potential in vitro nephrotoxic effects of four commonly abused cathinone derivatives, namely pentedrone, 3,4-dimethylmethcatinone (3,4-DMMC), methylone and 3,4-methylenedioxypyrovalerone (MDPV), were assessed in the human kidney HK-2 cell line. All four derivatives elicited cell death in a concentration- and time-dependent manner, in the following order of potency: 3,4-DMMC >> MDPV > methylone ≈ pentedrone. 3,4-DMMC and methylone were selected to further elucidate the mechanisms behind synthetic cathinones-induced cell death. Both drugs elicited apoptotic cell death and prompted the formation of acidic vesicular organelles and autophagosomes in HK-2 cells. Moreover, the autophagy inhibitor 3-methyladenine significantly potentiated cell death, indicating that autophagy may serve as a cell survival mechanism that protects renal cells against synthetic cathinones toxicity. Both drugs triggered a rise in reactive oxygen and nitrogen species formation, which was completely prevented by antioxidant treatment with N­acetyl­L­cysteine or ascorbic acid. Importantly, these antioxidant agents significantly aggravated renal cell death induced by cathinone derivatives, most likely due to their autophagy-blocking properties. Taken together, our results support an intricate control of cell survival/death modulated by oxidative stress, apoptosis and autophagy in synthetic cathinones-induced renal injury.


Assuntos
Alcaloides/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Drogas Ilícitas/toxicidade , Rim/efeitos dos fármacos , Alcaloides/química , Benzodioxóis/química , Benzodioxóis/toxicidade , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Rim/metabolismo , Rim/patologia , Metanfetamina/análogos & derivados , Metanfetamina/química , Metanfetamina/toxicidade , Metilaminas/química , Metilaminas/toxicidade , Pentanonas/química , Pentanonas/toxicidade , Pirrolidinas/química , Pirrolidinas/toxicidade , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
4.
Toxicol Appl Pharmacol ; 395: 114970, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234388

RESUMO

Synthetic cathinones, such as methylone and pentedrone, are psychoactive derivatives of cathinone, sold in the internet as "plant food" or "bath salts". However, the level at which these compounds and their enantiomers cross the intestinal barrier has not been yet determined. Thus, the present study aimed to analyze the enantioselectivity on the permeability of these drugs through the intestinal barrier by using the Caco-2 cell line, a widely used in vitro model for drug permeability studies. To achieve this goal, an UHPLC-UV method was developed and validated to quantify both synthetic cathinones. The developed UHPLC-UV method revealed high selectivity and a linearity from 1 to 500 µM with correlation coefficients always higher than 0.999. The method has an accuracy that ranged between 89 and 107%, inter-day and intra-day precisions with coefficients of variation below 10%, limits of detection and quantification of 0.31 µM and 0.93 µM for methylone and 0.17 µM and 0.52 µM for pentedrone, respectively. In Caco-2 cells, a differentiated passage of the enantiomers across monolayer was observed for both cathinones. For pentedrone, the difference was observed after the first hour, being R-(-)-pentedrone the most permeable compound. Regarding methylone, the difference was noted after one hour and 30 min, with S-(-)-methylone being the most absorbed enantiomer. In conclusion, a fully validated method was successfully applied for studying the permeability of methylone and pentedrone enantiomers in an in vitro model of human intestine, which allowed to discover, for the first time, the enantioselectivity in drug permeability of this class of drugs.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Absorção Intestinal/fisiologia , Metanfetamina/análogos & derivados , Metilaminas/química , Metilaminas/farmacocinética , Pentanonas/química , Pentanonas/farmacocinética , Alcaloides/química , Células CACO-2 , Humanos , Metanfetamina/química , Metanfetamina/farmacocinética , Permeabilidade , Psicotrópicos , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-Atividade
5.
J Anal Toxicol ; 44(6): 570-579, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32020200

RESUMO

Sampling and drug stability in oral fluid (OF) are crucial factors when interpreting forensic toxicological analysis, mainly because samples may not be analyzed immediately after collection, potentially altering drug concentrations. Therefore, the stability of some common drugs of abuse (morphine, codeine, 6-monoacetylmorphine, cocaine, benzoylecgonine, Δ9-tetrahydrocannabinol, cannabidiol, amphetamine, 3,4-methylenedioxymethamphetamine, ketamine) and the more commonly consumed new psychoactive substances in our environment (mephedrone, and N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide 5F-AKB48 also known as 5F-APINACA) was investigated in an OF pool for the presence and absence of M3 Reagent Buffer® up to 1 year of storage. Fortified OF samples were stored at three different temperatures (room temperature, 4 and -20°C) to determine the best storage conditions over time. Control fortified OF samples were stored at -80°C for reference purposes. Compounds with concentration changes within ±15% of initial value were considered stable. The drugs were significantly more stable in M3 Reagent Buffer® than in neat OF samples in all storage conditions. All analytes were stable for 1 year at 4°C and -20°C in M3 Reagent Buffer®. Drugs stability in OF varied depending on the analyte, the presence of a stabilizer, the storage duration and temperature. When immediate sample analysis is not possible, we suggest to store OF samples at 4 or -20°C and test them within 2 weeks. Alternatively, OF samples may be stored at 4 or -20°C with M3 Reagent Buffer® to be tested within 1 year.


Assuntos
Estabilidade de Medicamentos , Toxicologia Forense , Psicotrópicos/química , Detecção do Abuso de Substâncias , Anfetamina , Cocaína/análogos & derivados , Codeína , Drogas Ilícitas , Metanfetamina/análogos & derivados , Morfina , Derivados da Morfina , N-Metil-3,4-Metilenodioxianfetamina , Manejo de Espécimes
6.
PLoS One ; 15(1): e0227774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978078

RESUMO

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a ß-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.


Assuntos
Drogas Desenhadas/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Metanfetamina/análogos & derivados , Metanfetamina/efeitos adversos , Propiofenonas/efeitos adversos , Psicotrópicos/efeitos adversos , Animais , DNA Bacteriano/isolamento & purificação , Drogas Desenhadas/administração & dosagem , Feminino , Microbioma Gastrointestinal/genética , Metanfetamina/administração & dosagem , Camundongos , Modelos Animais , Propiofenonas/administração & dosagem , Psicotrópicos/administração & dosagem , RNA Ribossômico 16S/genética
7.
Drug Test Anal ; 12(4): 524-537, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31943846

RESUMO

The emergence of chemically masked illicit drugs represents a challenge to global initiatives that are working to prevent their manufacture and distribution. Targeted analytical techniques currently used by law enforcement to identify unknown materials rely on spectroscopic and spectrophotometric databases that do not currently include some of these compounds, making their identification challenging. This study aimed to update compound spectral libraries to aid in the rapid detection and identification of these masked drugs, as well as to provide insight into their synthetic procedures. Five commonly employed protecting groups, acetyl, p-tosyl, methoxycarbonyl, Fmoc, and t-Boc, were appended to pseudoephedrine, ephedrine, methamphetamine, and MDMA. Characterization was carried out using NMR, GC-MS, FTIR, high-resolution LC-MS/MS, and common screening color tests. Some of the methoxycarbonyl and t-Boc derivatives and all of the Fmoc derivatives showed partial or full thermal degradation or rearrangement during GC-MS analysis, while LC-MS/MS analysis did not always show characteristic fragmentation that would allow unambiguous assignment of the structure. Restricted rotation in some of the derivatives meant that NMR assignments could only be made using NMR spectra acquired at elevated temperature. Therefore, GC-MS and LC-MS/MS analyses serve complementary roles for these derivatives, with NMR providing confirmation of structure for the pure materials if necessary.


Assuntos
Efedrina/análogos & derivados , Drogas Ilícitas/análise , Metanfetamina/análogos & derivados , Pseudoefedrina/análogos & derivados , Cromatografia Líquida de Alta Pressão , Efedrina/análise , Cromatografia Gasosa-Espectrometria de Massas , Espectroscopia de Ressonância Magnética , Metanfetamina/análise , Pseudoefedrina/análise , Espectrometria de Massas em Tandem
8.
Sex Transm Infect ; 96(2): 124-130, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31171592

RESUMO

PURPOSE: Chemsex-related drug use (CDU) is an escalating public health issue among men who have sex with men (MSM), associated with significant physical, biomedical and psychosocial harm. Few interventions exist to help MSM engaging in chemsex and little data exist on which to build. This cross-sectional analysis, using data from Antidote, the UK's only lesbian, gay, bisexual, and transgender specialist drug service, aims to remedy this paucity of data. METHODS: Modified Poisson regression was used to assess associations between CDU and a range of health outcomes; CDU+ subanalysis disaggregated MSM by primary chemsex drug of concern; and HIV+ subanalysis investigated whether CDU was associated with self-reported treatment adherence, HIV seroconversion and other HIV-specific issues. FINDINGS: Compared with CDU- MSM, MSM presenting for CDU were more likely to be HIV+, current or previous injectors, to have used postexposure prophylaxis in the last year, and have had ≥6 sexual partners in the last 90 days, though less likely to be hazardous alcohol consumers or to have experienced previous suicidal ideation (all p<0.0005). CDU+ subanalysis revealed health outcome differences-those selecting mephedrone were less likely to be hepatitis C+, HIV+, current or previous injectors, or to have experienced previous suicidal ideation (all p<0.0005), whereas those selecting methamphetamine were more likely (all p<0.0005, except suicidal ideation p=0.009). IMPLICATIONS: This analysis shows MSM presenting for CDU are a heterogeneous high-risk population with unmet health needs. There is a need for standardised chemsex surveillance and for improved intersectorial working between sexual health and drug treatment services. Future research should investigate typological differences between MSM presenting for CDU. ORIGINALITY/VALUE: To date, this is the world's largest analysis of MSM seeking treatment for CDU. Further, the publication of 'real-world' service data is a valuable addition to the literature alongside surveys and recruited studies.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Infecções por HIV/epidemiologia , Hepatite C/epidemiologia , Metanfetamina , Comportamento Sexual/estatística & dados numéricos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Adulto , Fármacos Anti-HIV/uso terapêutico , Estudos Transversais , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Metanfetamina/análogos & derivados , Pessoa de Meia-Idade , Minorias Sexuais e de Gênero/psicologia , Abuso de Substâncias por Via Intravenosa/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Ideação Suicida , Reino Unido/epidemiologia , Adulto Jovem
9.
J Anal Toxicol ; 44(1): 92-102, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31436798

RESUMO

The production and consumption of new psychoactive substances (NPSs) has been raising a major concern worldwide. Due to easy access and available information, many NPSs continue to be synthesized with an alarming increase of those available to purchase, despite all the control efforts created. A new analytical method was developed and validated to determine a group of phenethylamines and synthetic cathinones: cathinone, flephedrone, buphedrone, 4-MTA, α-PVP, methylone, 2C-P, ethylone, pentylone, MDPV and bromo-dragonFLY in whole blood. A mixed-mode solid phase extraction was applied to 250 µL of sample, and the extracts were derivatized with fast microwave technique before being analyzed by gas chromatography-mass spectrometry (GC-MS). The validation procedure followed the Scientific Working Group for Forensic Toxicology (SWGTOX) guidelines with parameters that included selectivity, linearity, limits of detection and quantification, intra- and inter-day precision and accuracy, recoveries and stability. The method presented linearity between 5 and 500 ng/mL for cathinone, buphedrone, 4-MTA, methylone, 2C-P and bromo-dragonFLY, 10-500 ng/mL for flephedrone, ethylone, pentylone and MDPV, and 40-500 ng/mL for α-PVP, with determination coefficients above 0.99 for all analytes. Recoveries ranged between 70.3% and 116.6%, and regarding intra- and inter-day precision, the relative mean errors were typically lower than 8.6%. The method was successfully applied to over 100 authentic samples from the Laboratory of Chemistry and Forensic Toxicology, Centre Branch, of the National Institute of Legal Medicine and Forensic Sciences, Portugal.


Assuntos
Drogas Desenhadas/metabolismo , Toxicologia Forense , Micro-Ondas , Psicotrópicos/sangue , Detecção do Abuso de Substâncias/métodos , Acetona/análogos & derivados , Acetona/análise , Acetona/sangue , Alcaloides/análise , Alcaloides/sangue , Anfetaminas/análise , Anfetaminas/sangue , Drogas Desenhadas/análise , Etilaminas/análise , Etilaminas/sangue , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Metanfetamina/análogos & derivados , Metanfetamina/análise , Metanfetamina/sangue , Pentanonas/análise , Pentanonas/sangue , Fenetilaminas/análise , Fenetilaminas/sangue , Pirrolidinas/análise , Pirrolidinas/sangue
10.
Leg Med (Tokyo) ; 42: 101640, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751794

RESUMO

The chemsex or slamsex phenomenon has attracted attention worldwide, with concerns also expressed by health professionals for the spread of sexually transmitted diseases. Mephedrone or 4-methylmethcathinone, a substituted cathinone homolog of ephedrine, is one of the most popular substances used as a cheaper alternative to other traditional drugs. Fatal cases of chemsex are still rare. We present here the first case-report to the best of our knowledge of a mephedrone-related acute toxicity case in Parma (Italy) detected and quantitated in biological specimens (2.0 mg/L in urine sample, 1.1 mg/L in bile and 1.0 mg/L in central blood while 0.8 mg/L in peripheral blood). None of the other most common drugs of abuse could be detected. Autopsy findings such as facies edematosa, oedema and polyvisceral congestion, interstitial petechiae are compatible elements with a death from acute cardio-respiratory failure, with peri-mortem agony of few minutes in which the cardiac hypertrophy, the moderate aortocoronary sclerosis and mephedrone injection have played a substantial role in the evaluation of the final cause due to an accidental acute intoxication with mephedrone.


Assuntos
Metanfetamina/análogos & derivados , Autopsia , Evolução Fatal , Toxicologia Forense , Humanos , Masculino , Metanfetamina/sangue , Metanfetamina/envenenamento , Metanfetamina/toxicidade , Pessoa de Meia-Idade
11.
Fa Yi Xue Za Zhi ; 35(4): 419-422, 2019 Aug.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-31532149

RESUMO

Abstract: Objective To develop a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of the content of 4-fluoromethamphetamine (4-FMA) in rat plasma, and to provide a methodological basis for the study of the toxicokinetics of 4-FMA in rats. Methods Rat plasma samples were added into internal standard methamphetamine (MA). Its proteins were precipitated with methanol and then separated with Poroshell 120 EC-C18 chromatographic column. A 0.1% formic acid aqueous solution and a 0.1% formic acid acetonitrile solution were used as the mobile phase at the flow rate of 0.4 mL/min. Electrospray ionization source was used for detection in the multiple reaction monitoring (MRM) mode. Results The linear relationship was good when the mass concentration of 4-FMA in plasma samples was in the range of 5-1 000 ng/mL (r>0.999). The limit of detection (LOD) was 3 ng/mL and the limit of quantification (LOQ) was 5 ng/mL. The accuracy was expressed as relative error (RE), and in the range of ±5%, the intra-day precision and inter-day precision (relative standard deviation, RSD) less than 9%, and the extraction recovery rate was more than 90%. The analysis and detection of plasma samples were completed within 2.5 min. Conclusion This study developed a HPLC-MS/MS method for the determination of 4-FMA in rat plasma samples. This method is accurate, rapid, simple and sensitive and can be applied to the study of toxicokinetics of 4-FMA.


Assuntos
Cromatografia Líquida de Alta Pressão , Metanfetamina/sangue , Espectrometria de Massas em Tandem , Animais , Limite de Detecção , Metanfetamina/análogos & derivados , Ratos , Reprodutibilidade dos Testes , Toxicocinética
12.
Behav Pharmacol ; 30(7): 566-573, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31268871

RESUMO

Recreational abuse of illicit synthetic cathinones is an ongoing public health concern. Recent studies indicate that the methcathinone derivative 4-methylmethcathinone (4-MMC) produces behavioral and neurochemical effects similar to the entactogen 3,4-methylenedioxymethamphetamine (MDMA). Whereas polysubstance abuse is common, most preclinical studies of drug abuse liability only evaluate the effects of single drugs. Utilizing the locomotor sensitization paradigm, the present study assessed the combined locomotor stimulant effects of 4-MMC and MDMA for induction of sensitization following repeated administration and for expression of sensitization to a challenge dose of either substance alone after a 10-day period of drug abstinence. Male Sprague-Dawley rats received once daily intraperitoneal injections of saline, 4-MMC (1.0 mg/kg or 5.0 mg/kg), MDMA (3.0 mg/kg), or a mixture containing 4-MMC (1.0 mg/kg or 5.0 mg/kg) + MDMA (3.0 mg/kg) for 7 consecutive days. Following a 10-day drug-free period, rats were given a single intraperitoneal injection of either saline, 4-MMC (1.0 or 5.0 mg/kg), or 3.0 mg/kg MDMA. Activity was recorded for 1 h immediately before and 1 h immediately after injections on days 1, 7, and 17. 4-MMC treatment failed to induce locomotor sensitization, but, when combined with MDMA, sensitization was induced to a greater extent than with MDMA alone. Furthermore, the expression of sensitization to a subsequent challenge dose of MDMA was observed only in animals previously exposed to MDMA or a 5.0 mg/kg 4-MMC + MDMA mixture. In consideration of these findings along with the fact that 4-MMC has similar neurochemical actions to MDMA, further research may be warranted to determine the abuse liability of drug mixtures including 4-MMC and MDMA.


Assuntos
Locomoção/efeitos dos fármacos , Metanfetamina/análogos & derivados , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Alucinógenos/farmacologia , Injeções Intraperitoneais , Masculino , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
J Sep Sci ; 42(17): 2796-2804, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222942

RESUMO

A method for the preparation of novel mixed-mode reversed-phase/strong cation exchange stationary phase for the separation of fixed-dose combination drugs has been developed. An epoxysilane bonded silica prepared by vapor phase deposition was used as a starting material to produce diol, octadecyl, sulfonate, and mixed octadecyl/sulfonate groups bonded silica phases. The chemical structure and surface coverage of the functional groups on these synthesized phases were confirmed by fourier-transform infrared and solid-state 13 C NMR spectroscopy and elemental analysis. Alkylbenzene homologs, basic drugs, nucleobases and alkylaniline homologs were used as probes to demonstrate the reversed-phase, ion exchange, hydrophilic interaction and mixed-mode retention behaviors of these stationary phases. The octadecyl/sulfonate bonded silica exhibits pronounced mixed-mode retention behavior and superior retentivity and selectivity for alkylaniline homologs. The mixed-mode retention is affected by either ionic or solvent strength in the mobile phase, permiting optimization of a separation by fine tuning these parameters. The mixed-mode stationary phase was applied to separate two fixed-dose combination drugs: compound reserpine tablets and compound methoxyphenamine capsules. The results show that simultaneous separation of multiple substances in the compound dosage can be achieved on the mixed-mode phase, which makes multi-cycles of analysis for multiple components obsolete.


Assuntos
Compostos de Epóxi/química , Metanfetamina/análogos & derivados , Reserpina/isolamento & purificação , Cápsulas/química , Cápsulas/isolamento & purificação , Cromatografia de Fase Reversa , Metanfetamina/química , Metanfetamina/isolamento & purificação , Estrutura Molecular , Reserpina/química , Dióxido de Silício/química , Comprimidos/química , Comprimidos/isolamento & purificação
15.
Neurochem Int ; 129: 104487, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176680

RESUMO

Repeated exposure to classical psychomotor stimulants, like amphetamine (AMPH), produces locomotor sensitization and accompanied structural plasticity of dendritic spines in the nucleus accumbens (NAcc). Following our previous report that repeated administration of methiopropamine (MPA), a structural analog to meth-AMPH, produces locomotor sensitization, it was examined in the present study whether this behavioral change also accompanies with structural plasticity in the NAcc in a similar way to AMPH. A week after adeno-associated viral vectors containing enhanced green fluorescent protein (eGFP) were microinjected into the NAcc core, rats were repeatedly injected with saline, AMPH (1 mg/kg, IP), or MPA (5 mg/kg, IP) once every 2-3 days for a total of 4 times. Two weeks after last injection, all rats were perfused and their brains were processed for immunohistochemical staining. The image stacks for dendrite segments of medium spiny neuronal cells in the NAcc core were obtained and dendritic spines were quantitatively analyzed. Interestingly, it was found that the number of total spine density, with thin spine as a major contributor, was significantly increased in MPA compared to saline pre-exposed group, in a similar way to AMPH. These results indicate that MPA, a novel psychoactive substance, has similar characteristics with AMPH in that they both produce structural as well as behavioral changes, further supporting MPA's dependence and abuse potential.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Metanfetamina/análogos & derivados , Núcleo Accumbens/efeitos dos fármacos , Tiofenos/farmacologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Espinhas Dendríticas/ultraestrutura , Genes Reporter , Masculino , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/ultraestrutura , Ratos , Ratos Sprague-Dawley
16.
Basic Clin Pharmacol Toxicol ; 125(3): 253-258, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31188528

RESUMO

Urine tests are the commonly accepted methods to control abstinence and adherence to treatment of patients who undergo methadone maintenance treatment (MMT). Depending on various national guidelines and accessibility of techniques, only selected psychoactive substances are routinely tested in urine of MMT patients. In general, they belong to the few groups of compounds: THC, cocaine, amphetamines, opiates, PCP and benzodiazepines. It is, however, well known that patients enrolled in such replacement programmes take psychoactive substances that are not routinely detected by the toxicology laboratories, to escape unexpected tests. Here, we report semiquantitative detection of legal highs taken by the MMT patient, using high-pressure liquid chromatography coupled to the flowing atmospheric pressure afterglow ion source (LC-FAPA-MS). To demonstrate effectivity of this technique, the data were confirmed by quantitative analysis using LC-ESI-MS/MS. In the analysed sample of MMT patient, a mixture of psychoactive compounds was found, namely 3-MMC (3-methylmethcathinone), pentedrone and methcathinone and determined at the concentrations of 670; 50 and 0.2 µg/mL, respectively. Such fast analytical technique may be useful for the efficient control of substances taken intentionally by MMT patients.


Assuntos
Metadona/uso terapêutico , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Psicotrópicos/urina , Detecção do Abuso de Substâncias/métodos , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Limite de Detecção , Metanfetamina/análogos & derivados , Metanfetamina/urina , Metilaminas/urina , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/urina , Cooperação do Paciente , Pentanonas/urina , Propiofenonas/urina , Espectrometria de Massas em Tandem/métodos
17.
Electrophoresis ; 40(14): 1762-1770, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31093983

RESUMO

This work presents a strategy based on the in-line coupling of SPE and CE for the chiral determination of cathinones (R,S-mephedrone, R,S-4-methylephedrine, and R,S- methylenedioxypyrovalerone) in urine samples, using a sample pretreatment based on liquid-liquid extraction. The chiral separation of the compounds is achieved by adding a mixture of 8 mM 2-hydroxypropil ß-CD and 5 mM ß-CD to the BGE, which consists of 70 mM of monosodium phosphate aqueous solution at pH 2.5. Oasis HLB was the selected sorbent for the in-line SPE device, and to reduce analysis time and LODs, several parameters affecting the in-line SPE system were evaluated, such as pressure and time of sample injection and dimensions of the SPE device. The highest preconcentration factors were achieved by using 3 bar of injection pressure for 20 min with an in-line SPE device of 2 mm length and 150 µm of i.d. The developed method was applied to determine the presence of the compounds in spiked urine samples. The LODs obtained were between 3 and 8 ng/mL, and these levels were below the usual concentrations at which these drugs are present in urine from cathinone abusers. Thus, the optimized method has the potential to be applied for toxicological and forensic purposes.


Assuntos
Alcaloides/urina , Eletroforese Capilar , Extração em Fase Sólida , Benzodioxóis/análise , Eletroforese Capilar/métodos , Efedrina/análogos & derivados , Efedrina/análise , Humanos , Limite de Detecção , Extração Líquido-Líquido/métodos , Metanfetamina/análogos & derivados , Metanfetamina/análise , Pirrolidinas/análise , Reprodutibilidade dos Testes , Extração em Fase Sólida/métodos , Estereoisomerismo
18.
Forensic Sci Int ; 300: e34-e37, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31056341

RESUMO

The significant increase in the number of new psychoactive substances on the drug market has recently been a serious problem. The manuscript presents a fatal case of suicide poisoning with 3-MMC (3-methylmethcathinone). The biological material collected during the autopsy of a 19-year-old woman, transferred to the toxicological Laboratory in Katowice ToxLab, was subjected to a chemical and toxicological analysis. The toxicological analysis of blood, vitreous humor and gastric contents revealed 3-methylmetcatinone at a concentration of 800 ng/ml, 153 ng/ml and 5,5 mg, respectively. The presence of 3-MMC has also been confirmed in physical evidence secured on site. 3-methylmethcathinone is a dangerous psychoactive substance that caused the death of the 19-year-old.


Assuntos
Drogas Desenhadas/envenenamento , Metanfetamina/análogos & derivados , Psicotrópicos/envenenamento , Drogas Desenhadas/análise , Feminino , Conteúdo Gastrointestinal/química , Humanos , Metanfetamina/análise , Metanfetamina/envenenamento , Psicotrópicos/análise , Suicídio , Corpo Vítreo/química , Adulto Jovem
19.
Forensic Sci Int ; 301: 67-75, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129374

RESUMO

In order to investigate the influence of pigmentation on the incorporation of drugs into hair, time-course changes in drug distribution along non-pigmented (white) hairs as well as pigmented (black) hairs plucked from the same subject was observed following single administrations of two basic drugs with different properties, zolpidem and methoxyphenamine. These drugs in 1-mm sections of single hair specimens were each determined by a liquid chromatography-tandem mass spectrometric procedure. During the early stage (12-36 h) after intake, for black hairs, both drugs were detected over the entire area of hair root (4-5 mm in length), in which notable concentration of these drugs in the hair bulb (0-1-mm segment from the bottom of hair root, Region 1) and lower concentrations in the upper dermis zone (1-2-mm to 3-4-mm or to 4-5-mm segments, Region 2) were commonly observed. Meanwhile, for white hairs, high drug concentrations in Region 1 as detected in black hairs were not observed although only small amounts of these drugs were detected over Region 2. Subsequent time-course changes in the concentration of drugs in hair demonstrated that the drugs once incorporated into white hair via Region 2 decreased gradually over the period from 24 h to 35 days after intake, but those of black hairs remained almost unchanged. These findings revealed here suggest that hair pigments have two important roles in the distribution of drugs: (1) incorporation of drugs into hair via Region 1, and (2) retention of already incorporated drugs in the hair tissue. These findings would be useful for discussing individual drug-use history based on hair analysis in the forensic fields.


Assuntos
Cor de Cabelo , Cabelo/química , Metanfetamina/análogos & derivados , Zolpidem/análise , Cromatografia Líquida , Toxicologia Forense , Humanos , Hipnóticos e Sedativos/análise , Masculino , Metanfetamina/análise , Pessoa de Meia-Idade , Entorpecentes/análise , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem , Fatores de Tempo
20.
Psychopharmacology (Berl) ; 236(3): 1015-1029, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30980094

RESUMO

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.


Assuntos
Alcaloides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Metanfetamina/análogos & derivados , Antagonistas da Serotonina/farmacologia , Animais , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/fisiologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Drogas Ilícitas/farmacologia , Ketanserina/farmacologia , Masculino , Metanfetamina/farmacologia , Psicotrópicos/farmacologia , Ratos , Ratos Sprague-Dawley
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