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1.
Fa Yi Xue Za Zhi ; 36(5): 677-681, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33295170

RESUMO

Abstract: Objective To study the identification method for 4'-F-4-methylaminorex (4'-F-4-MAR) in samples without reference substance. Methods Gas chromatography-mass spectrometry (GC-MS), ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS), nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) were comprehensively used for the structure identification of 4'-F-4-MAR in samples. Results Under the positive electrospray ionization (ESI+) mode, quasi-molecular ion in the first order mass spectrometry of the unknown compound was 195.092 6 and its molecular formula was inferred to be C10H11FN2O. The fragment ions in the mass spectrometry of the unknown compound were compared with the related fragment ions of 4,4'-dimethylaminorex (4,4'-DMAR) in literature. It was found that the main fragment ions of the unknown compound were all 4 bigger than the corresponding fragment ions of 4,4'-DMAR. Therefore, the unknown compound was inferred to be a 4,4'-DMAR analogue with a methyl substituted by a fluorine in the benzene ring. The equivalent protons at δ=7.30 and δ=7.06 in 1H-nuclear magnetic resonance (1H-NMR) spectra and the characteristic spin-spin coupling constants (1JC-F=245.2 Hz, 2JC-F=21.3 Hz, 3JC-F=8.1 Hz) for 13C-19F interactions in carbon spectra, further proved that the fluorine substituted methyl at the para-position of the benzene ring. Finally, the unknown compound was determined as 4'-F-4-MAR. Conclusion A method that comprehensively used the identification materials 4'-F-4-MAR in GC-MS, UPLC-QTOF-MS, NMR and FTIR is established and the fragmentation mechanism of fragmentation ions of 4'-F-4-MAR created under the two modes -- electron impact (EI) and electrospray ionization under collision induced dissociation (ESI-CID) is deduced. The information will assist forensic science laboratories in identifying this compound or other substances with similar structure in their case work.


Assuntos
Aminorex , Espectrometria de Massas por Ionização por Electrospray , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Espectrometria de Massas , Nitroimidazóis
2.
Drug Test Anal ; 12(10): 1477-1482, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32567235

RESUMO

Aminorex is a US DEA Schedule 1 controlled substance occasionally detected in racing horses. A number of aminorex identifications in sport horses were thought to have been caused by exposure to plant sources of aminorex. Glucobarbarin, found in plants of the Brassicaceae family, has been suggested as a potential proximate chemical source by being metabolized in the plant or the horse to aminorex. In Brassicaceae, glucobarbarin is hydrolyzed by myrosinase to yield barbarin, which serves as an insect repellant and/or attractant and is structurally related to aminorex. The synthesis, purification, and characterization of barbarin is now reported for use as a reference standard in aminorex related research concerning equine urinary identifications of aminorex and also for possible use in equine administration experiments. Synthesis of barbarin was performed via ring closure between phenylethanolamine and carbon disulfide in tetrahydrofuran with the catalyst pyridine under reflux. The reaction yielded a white crystalline substance that was purified and chemically characterized as barbarin for use as a Certified Reference Standard or for studies related to equine aminorex identification.


Assuntos
Aminorex/análise , Drogas Ilícitas/análise , Oxazóis/síntese química , Animais , Técnicas de Química Sintética , Doping nos Esportes , Ciências Forenses , Cavalos , Oxazóis/análise , Padrões de Referência , Detecção do Abuso de Substâncias/normas
3.
Neurotoxicology ; 72: 95-100, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30776375

RESUMO

4,4'-Dimethylaminorex (4,4'-DMAR) is a novel psychoactive substance (NPS) that appeared on the illicit drug market in addition to the psychostimulant 4-methylaminorex (4-MAR). Both substances are methylated derivatives of aminorex, an amphetamine-like anorectic used in the 1960ies and withdrawn from the marked due to severe cardiovascular toxicity. The aim of the present study was to characterize the in vitro pharmacological profiles of 4-MAR, 4,4'-DMAR, and 3,4-dimethylaminorex (3,4-DMAR, direx). We assessed norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney (HEK) 293 cells. We also assessed monoamine receptor and transporter binding affinities. 4,4'-DMAR potently inhibited all monoamine transporters (IC50<1 µM) with greater potency than 3,4-methlyenedioxymethamphetaime (MDMA) and displayed a higher serotonergic over dopaminergic preference, relatively similar to MDMA (DA transporter / 5-HT transporter inhibition ratio of 0.4 and 0.08 for 4,4'-DMAR and MDMA, respectively). In contrast, 4-MAR preferentially inhibited the NE and DA transporter, exhibiting a pharmacological profile more similar to amphetamine. Both 4-MAR and 4,4'-DMAR were also substrate releasers at the DAT. 3,4-DMAR only weakly inhibited the NE transporter and showed no relevant activity at the DA and 5-HT transporter. Binding affinities of all three aminorex derivatives at various monoamine receptors were negligible (Ki values >2 µM). The in vitro pharmacological profiles indicate that 4,4'-DMAR has comparable psychoactive properties and serotonergic toxicity to MDMA and may be more potent. 4-MAR is a psychostimulant similar to amphetamine or methamphetamine. 3,4-DMAR likely has only weak psychostimulant properties.


Assuntos
Aminorex/análogos & derivados , Aminorex/farmacologia , Monoaminas Biogênicas/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células HEK293 , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/administração & dosagem
4.
J Anal Toxicol ; 43(4): 299-306, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590551

RESUMO

Aminorex has been reported as a metabolite of levamisole in man, but data on the aminorex concentrations in clinical samples are scant. We thus measured levamisole, aminorex and benzoylecgonine in urine, and levamisole and aminorex in plasma using achiral liquid chromatography-high resolution mass spectrometry. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standard (benzoylecgonine-D3, 25 µg/L) (450 µL). For plasma, sample (200 µL) and Tris solution (2 mol/L, pH 10.6, 100 µL) were added to a 60.5 × 7.5 mm i.d. glass test tube. Internal standard solution (ketamine-D4, 200 µg/L) (10 µL) was added and the tube contents vortex-mixed (5 s). Butyl acetate:butanol (9 + 1, v/v; 200 µL) was added and after vortex-mixing (30 s) and centrifugation (13,680 × g, 4 min), the extract was evaporated to dryness and reconstituted in 10 mmol/L aqueous ammonium formate containing 0.1% (v/v) formic acid (150 µL). Prepared samples and extracts (100 µL) were analyzed using an AccucoreTM Phenyl-Hexyl column (2.6 mm a.p.s., 100 × 2.1 mm i.d.) maintained at 40°C. MS detection was in positive mode using heated electrospray ionization (ThermoFisher Q-ExactiveTM). Intra- and inter-assay accuracy and precision were ±20%, and ≤11%, respectively, for all analytes in both matrices. Lower limits of quantitation were 0.1 and 1 µg/L (all analytes) in plasma and urine, respectively. Of 100 consecutive urine samples submitted for drugs of abuse screening containing benzoylecgonine, levamisole was detected in 72 (median 565, range 4-72,970 µg/L). Levamisole was also measured in eight plasma samples (median 10.6, range 0.9-64.1 µg/L). A number of metabolites of levamisole (4-hydroxylevamisole, levamisole sulfoxide, levamisole glucuronide, and hydroxylevamisole glucuronide) were tentatively identified in urine. Neither aminorex, nor any of its reported metabolites were detected in any sample.


Assuntos
Aminorex/sangue , Aminorex/urina , Antinematódeos/sangue , Antinematódeos/urina , Depressores do Apetite/sangue , Depressores do Apetite/urina , Cocaína/análogos & derivados , Levamisol/sangue , Levamisol/urina , Detecção do Abuso de Substâncias/métodos , Vasoconstritores/urina , Adulto , Idoso , Agranulocitose/etiologia , Antinematódeos/efeitos adversos , Antinematódeos/química , Cromatografia Líquida , Cocaína/urina , Contaminação de Medicamentos , Feminino , Meia-Vida , Humanos , Drogas Ilícitas , Levamisol/efeitos adversos , Levamisol/química , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Espectrometria de Massas em Tandem , Vasculite/etiologia , Adulto Jovem
5.
ACS Chem Neurosci ; 9(10): 2484-2502, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30269490

RESUMO

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.


Assuntos
Aminorex/análogos & derivados , Aminorex/química , Aminorex/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Drogas Desenhadas , Aminorex/história , Estimulantes do Sistema Nervoso Central/história , História do Século XX , História do Século XXI , Humanos
6.
J Chem Neuroanat ; 83-84: 75-81, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28619473

RESUMO

Cocaine is a naturally occurring and illicitly used psychostimulant drug. Cocaine acts at monoaminergic neurotransmitter transporters to block uptake of the monoamines, dopamine, serotonin and norepinephrine. The resulting increase of monoamines in the extracellular space underlies the positively reinforcing effects that cocaine users seek. In turn, this increase in monoamines underlies the development of addiction, and can also result in a number of severe side effects. Currently, cocaine is one of the most common illicit drugs available on the European market. However, cocaine is increasingly sold in impure forms. This trend is driven by cocaine dealers seeking to increase their profit margin by mixing ("cutting") cocaine with numerous other compounds ("adulterants"). Importantly, these undeclared compounds put cocaine consumers at risk, because consumers are not aware of the additional potential threats to their health. This review describes adulterants that have been identified in cocaine sold on the street market. Their typical pharmacological profile and possible reasons why these compounds can be used as cutting agents will be discussed. Since a subset of these adulterants has been found to exert effects similar to cocaine itself, we will discuss levamisole, the most frequently used cocaine cutting agent today, and its metabolite aminorex.


Assuntos
Cocaína , Contaminação de Medicamentos , Aminorex/farmacologia , Humanos , Levamisol/farmacologia
7.
Anal Chim Acta ; 934: 239-51, 2016 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-27506366

RESUMO

In order to assess the true impact of each single enantiomer of pharmacologically active compounds (PACs) in the environment, highly efficient, fast and sensitive analytical methods are needed. For the first time this paper focuses on the use of ultrahigh performance supercritical fluid based chromatography coupled to a triple quadrupole mass spectrometer to develop multi-residue enantioselective methods for chiral PACs in environmental matrices. This technique exploits the advantages of supercritical fluid chromatography, ultrahigh performance liquid chromatography and mass spectrometry. Two coated modified 2.5 µm-polysaccharide-based chiral stationary phases were investigated: an amylose tris-3,5-dimethylphenylcarbamate column and a cellulose tris-3-chloro-4-methylphenylcarbamate column. The effect of different chromatographic variables on chiral recognition is highlighted. This novel approach resulted in the baseline resolution of 13 enantiomers PACs (aminorex, carprofen, chloramphenicol, 3-N-dechloroethylifosfamide, flurbiprofen, 2-hydroxyibuprofen, ifosfamide, imazalil, naproxen, ofloxacin, omeprazole, praziquantel and tetramisole) and partial resolution of 2 enantiomers PACs (ibuprofen and indoprofen) under fast-gradient conditions (<10 min analysis time). The overall performance of the methods was satisfactory. The applicability of the methods was tested on influent and effluent wastewater samples. To the best of our knowledge, this is the first feasibility study on the simultaneous separation of chemically diverse chiral PACs in environmental matrices using ultrahigh performance supercritical fluid based chromatography coupled with tandem mass spectrometry.


Assuntos
Cromatografia com Fluido Supercrítico , Poluentes Químicos da Água/análise , Aminorex/análise , Carbazóis/análise , Cloranfenicol/análise , Cromatografia Líquida de Alta Pressão , Flurbiprofeno/análise , Humanos , Ibuprofeno/análise , Ifosfamida/análise , Imidazóis/análise , Indoprofen/análise , Estrutura Molecular , Naproxeno/análise , Ofloxacino/análise , Omeprazol/análise , Praziquantel/análise , Extração em Fase Sólida , Estereoisomerismo , Espectrometria de Massas em Tandem , Tetramizol/análise
8.
Clin Toxicol (Phila) ; 53(7): 604-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26065363

RESUMO

CONTEXT: The prevalence of levamisole in urine samples of subjects positive for cocaine in the US was estimated at 78% (95%confidence interval or CI: 73%-83%). However, levamisole was not quantified, and at the time of this report, aminorex was not known to be a possible metabolite of levamisole in human. Moreover no data are available in Europe. OBJECTIVE: The aim of this study was to determine the prevalence and concentration of levamisole and aminorex in positive cocaine urine toxicology tests, and in serum samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies. MATERIALS AND METHODS: Consecutive urine toxicology samples tested positive for cocaine by immunoassay (EMIT, Siemens) from April to May 2014 at the toxicology laboratory of a French University Hospital, and blood samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies from April to December 2014 were analyzed by liquid chromatography-tandem mass spectrometry or LC-MS/MS (3200 QTrap, AB Sciex) to detect and quantify the presence of levamisole and aminorex. RESULTS: Forty-two urine samples tested positive for cocaine in 39 patients (79.5% males) with a median age of 43 [range: 20-51] years. Toxicological analyses were mainly required by addictions care centers (n = 17; 40%) in the context of the routine management of addict patients. Cocaine concentrations were above the limit of quantification for 33 patients, with a median value of 228 [0-645,000] ng/ml. Levamisole was detected in 32 urine samples (76%) (median concentration: 1,430 ng/ml, range: 30-258,000). Aminorex was never detected. During the study period, levamisole was detected in 87.5% of cocaine-positive blood samples of the subjects driving under the influence of drugs or forensic autopsies. DISCUSSION: In this prospective study, the prevalence of levamisole in cocaine-positive samples was 76%. Over this period, although clinical complications related to cocaine use were reported (agitation, road accident, and cardiac arrest), no complication specifically related to levamisole or aminorex was reported. CONCLUSION: Our results show a high prevalence of levamisole in samples of subjects positive for cocaine, close to the prevalence found in the US. This high prevalence raises issues with respect to well-identified health risks associated with regular consumption of levamisole.


Assuntos
Aminorex/urina , Cocaína/urina , Levamisol/urina , Adulto , Cromatografia Líquida , Transtornos Relacionados ao Uso de Cocaína/urina , Europa (Continente) , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espectrometria de Massas em Tandem , Adulto Jovem
9.
Drug Test Anal ; 7(7): 555-64, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25331619

RESUMO

The recent occurrence of deaths associated with the psychostimulant cis-4,4'-dimethylaminorex (4,4'-DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4-methylenedioxy-4-methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis- and trans-MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis-isomer (90%). Exposure of the cis-isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans-isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non-selective monoamine releasing agent (+)-3,4-methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis- and trans-4,4'-DMAR, were assessed under identical conditions. cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR were more potent than MDMA in their ability to function as efficacious substrate-type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR and trans-MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans-4,4'-DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring-substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side-effects after high dose exposure.


Assuntos
Aminorex/análogos & derivados , Aminorex/síntese química , Estimulantes do Sistema Nervoso Central/síntese química , Proteínas Vesiculares de Transporte de Monoamina/efeitos dos fármacos , Aminorex/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Cristalografia por Raios X , Masculino , Psicotrópicos , Ratos , Ratos Sprague-Dawley , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
10.
J Med Toxicol ; 11(1): 80-4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25167967

RESUMO

4,4'-Dimethylaminorex is a stimulant novel psychoactive substance (NPS) first detected in Europe in November 2012. It is a derivative of 4-methylaminorex, a substance controlled under Schedule 1 of the 1971 United Nations Convention on Psychotropic Substances. There is currently no information on the availability or cost of these substances from Internet suppliers. An Internet snapshot study was undertaken in English using established European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) methodology to determine the availability of 4-methylaminorex and 4,4'-dimethylaminorex in April 2014. Twenty Internet sites selling 4-methylaminorex were identified, 18 selling in US dollars and two in GB Pound Sterling. Fourteen (70 %) Internet sites had a minimum purchase amount of ≥10 g (compared to user doses of 10-25 mg). For the 18 suppliers selling in US$, 9 quoted a fixed price per gram irrespective of the amount ordered and 11 had a reducing price per gram with increasing purchase quantity (US$30.8 ± 34.2/g for 1 g purchase to US$15.2 ± 20.3/g for 1 kg purchase). Only one Internet site selling 4,4'-dimethylaminorex was identified, selling in Euros. The minimum purchase quantity was 500 mg. The price per gram reduced from 36.08/g for a 500 mg purchase to 2.20/g for a 100 g purchase. This Internet snapshot demonstrated that there was a greater availability from Internet suppliers of products advertised as 4-methylaminorex than 4,4'-dimethylaminorex, despite the 4-methylaminorex being an internationally controlled substance. Whilst this may reflect misunderstanding by suppliers, it has the potential to put those purchasing at risk of contravening border control and/or local law enforcement legislation. The use of methodology such as Internet snapshot surveys is of increasing interest to clinical/medical toxicologists in their understanding of the supply, availability and cost of novel psychoactive substances.


Assuntos
Aminorex/análogos & derivados , Drogas Desenhadas/provisão & distribuição , Tráfico de Drogas , Drogas Ilícitas/provisão & distribuição , Oxazóis/provisão & distribuição , Aminorex/economia , Aminorex/provisão & distribuição , Drogas Desenhadas/economia , Custos de Medicamentos , Tráfico de Drogas/economia , Europa (Continente) , Toxicologia Forense/métodos , Humanos , Drogas Ilícitas/economia , Internet , Aplicação da Lei/métodos , Metilação , Oxazóis/economia , Pós , Vigilância em Saúde Pública/métodos , Ferramenta de Busca , Toxicologia/métodos
11.
Forensic Sci Int ; 240: e7-10, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24794740

RESUMO

The conversion of levamisole to aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world's seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05ng/mL; blood, 15.05ng/mL; brain, >0.15ng/g; liver, >0.15ng/g; hair, 12.15ngmg; aminorex: urine, 38.62ng/mL; blood, 8.92ng/mL, brain >0.15ng/g; liver, 0.15ng/g; hair 7.35ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder.


Assuntos
Aminorex/efeitos adversos , Depressores do Apetite/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/complicações , Hipertensão Pulmonar/induzido quimicamente , Aminorex/análise , Depressores do Apetite/análise , Usuários de Drogas , Patologia Legal , Cabelo/química , Humanos , Levamisol/análise , Pulmão/patologia , Masculino , Pessoa de Meia-Idade
12.
Drug Test Anal ; 6(10): 1049-54, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24574157

RESUMO

Levamisole is an anti-helminthic drug and gained forensic interest after it was found that it was used as a cocaine adulterant. A liquid chromatography-mass spectrometry (LC-MS) method for the determination of levamisole and its metabolite aminorex in human plasma is described. Selectivity is given; calibration curves were linear within a calibration range of 1 ng/mL-500 ng/mL. Limits of detection and quantification (LODs, LOQs) were 0.85 ng/mL for levamisole and 0.09 ng/mL, and 0.34 ng/mL for aminorex, respectively. Precision data was in accordance with the GTFCh guidelines. The validated method was successfully applied to study the pharmacokinetics of levamisole after administration of 100 mg of levamisole orally. Levamisole could be detected up to 36 h after ingestion in serum, while aminorex never exceeded the LOQ. A one-compartment model best described levamisole pharmacokinetics. The following parameters were calculated: ka = 1.2 [1/h], CL/F = 52 l/h, V/F = 347 l, f (renal) = 0.0005, t ½ = 2.0 h, AUC = 1923 ng/mL*h, cmax = 214 ng/mL, tmax = 1.98 h. Levamisole could be quantified in 42.5% of cocaine--positive plasma samples (2.2 to 224 ng/mL). Aminorex was positive in only 11.3% of the cases; however, it was never found higher than the LOQ. Pemoline, another stimulant detected in horse urine samples after administration of levamisole, was not found either in serum or in urine of this pharmacokinetic study. In post-mortem cases, levamisole and aminorex could be detected in femoral blood and the urine of cocaine users. Pemoline was not detected.


Assuntos
Aminorex/análise , Cromatografia Líquida/métodos , Levamisol/farmacocinética , Espectrometria de Massas/métodos , Administração Oral , Adulto , Aminorex/metabolismo , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/análise , Anti-Helmínticos/farmacocinética , Área Sob a Curva , Meia-Vida , Humanos , Levamisol/administração & dosagem , Levamisol/análise , Limite de Detecção , Masculino , Modelos Biológicos , Pemolina/análise
13.
Neurochem Int ; 73: 32-41, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24296074

RESUMO

Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30µM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect "fades out" the levamisole/aminorex effect "kicks in".


Assuntos
Aminorex/farmacologia , Anfetamina/farmacologia , Depressores do Apetite/farmacologia , Cocaína/química , Levamisol/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Contaminação de Medicamentos , Células HEK293 , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos
14.
Semin Respir Crit Care Med ; 34(5): 560-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24037625

RESUMO

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Vasodilatadores/uso terapêutico , Aminorex/efeitos adversos , Depressores do Apetite/efeitos adversos , Bosentana , Dasatinibe , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Hipertensão Pulmonar Primária Familiar , Fenfluramina/efeitos adversos , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/etiologia , Iloprosta/uso terapêutico , Fenilpropionatos/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Fatores de Risco , Citrato de Sildenafila , Sulfonamidas/uso terapêutico , Sulfonas/uso terapêutico , Tiazóis/efeitos adversos
15.
Anal Bioanal Chem ; 405(12): 4077-88, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23436169

RESUMO

The antihelminthic drug Levamisole can enhance cocaine effects by conversion into the amphetamine-like drug aminorex. We describe an LC-MS method for the determination of levamisole and its metabolite aminorex in human urine. Selectivity is given, calibration curves were linear within the calibration range 2.5-250 ng/mL; limits of the method were LoD 0.51 ng/mL, LoQ 1.02 ng/mL for levamisole and LoD 0.65 ng/mL, LoQ 0.76 ng/mL for aminorex. Precision data was in accordance with the guidelines (intraday precision for aminorex ranged between 5.75 and 11.0 % for levamisole between 8.36 and 10.9 %; interday precision for levamisole 10.9-16.9 % and for aminorex 7.64-12.7 %; accuracy data for levamisole -1.96 to -14.3 % and for aminorex-11.9 to-18.5 %). The validated method was successfully applied to study the urinary excretion of levamisole after the administration of 100 mg of levamisole orally. Levamisole and aminorex could be detected in post-administration urine samples. Levamisole could be detected up to 39 h after ingestion, while aminorex was detectable up to 54 h. Maximum aminorex concentrations were 45 ng/mL urine. Further metabolites of levamisole after oral ingestion by means of liquid chromatography hybrid quadrupole time-of-flight high-resolution mass spectrometry (LC-QTOF-HRMS) were identified. Only 0.5 % of the ingested drug was quantified as unchanged levamisole in urine. Besides aminorex, five isomers of aminorex and 4 hydroxy-metabolites of aminorex or its isomers were found. Furthermore, levamisole is also hydroxylated and eliminated free or conjugated with sulfate or glucuronide into urine.


Assuntos
Aminorex/urina , Anti-Helmínticos/metabolismo , Anti-Helmínticos/urina , Levamisol/metabolismo , Levamisol/urina , Espectrometria de Massas em Tandem/métodos , Aminorex/metabolismo , Anti-Helmínticos/administração & dosagem , Cromatografia Líquida/métodos , Humanos , Levamisol/administração & dosagem , Limite de Detecção
16.
Int J Cardiol ; 158(3): 344-6, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-21764154

RESUMO

Levamisole is found in more than 80% of illicit cocaine seized within United States borders. Percentages are somewhat lower in Europe. In 2009, controlled in vivo studies demonstrated that horses metabolize levamisole to aminorex. Earlier this year our laboratory demonstrated that the same conversion occurs in man. Levamisole itself causes aplastic anemia and numerous reports have begun to appear in the literature, but the conversion of levamisole to aminorex is of much more concern. Aminorex ingestion was responsible for a five-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) confined to Switzerland, Austria, and Germany, the only countries where aminorex had been marketed as an anorectic. The incidence of IPH reverted to normal levels as soon as aminorex was withdrawn. In most cases onset of symptoms in IPH began after six to nine months of aminorex use, with average dosage ranges of 10 to 40 mg per day. The outcome was almost uniformly fatal. The conversion rate of levamisole to aminorex has not been established, but given the high daily intake of cocaine by many abusers, it seems likely that many of them will have ingested enough contaminated cocaine to ultimately cause IPH. Until the disease is well established, the symptoms of IHP are vague, and existing drug registries specifically exclude drug abusers, making it difficult to track these cases. This review is intended to draw attention to what may be a slowly emerging new epidemic.


Assuntos
Aminorex/envenenamento , Depressores do Apetite/envenenamento , Transtornos Relacionados ao Uso de Cocaína/epidemiologia , Epidemias/estatística & dados numéricos , Hipertensão Pulmonar/induzido quimicamente , Aminorex/metabolismo , Antirreumáticos/farmacocinética , Antirreumáticos/envenenamento , Depressores do Apetite/metabolismo , Contaminação de Medicamentos , Hipertensão Pulmonar Primária Familiar , Humanos , Levamisol/farmacocinética , Levamisol/envenenamento
17.
J Pharm Biomed Anal ; 55(5): 1186-9, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21531521

RESUMO

The Drug Enforcement Administration (DEA) reports that as of October 2010, 79% of all cocaine seized in the United States contained levamisole. The equine conversion of levamisole to aminorex has been demonstrated. However, the metabolic fate of levamisole in humans is unknown. Nevertheless, as aminorex is amphetamine-like and hallucinogenic, it may be used as an adulterant to increase the effects of cocaine. We report here the results of in vivo studies demonstrating for the first time that not only equine, but also canine and human metabolism all result in aminorex formation. Levamisole and aminorex were extracted from real urine samples by liquid-liquid extraction and identified and quantified by GC-MS (identification by 3 ions per substance, LLOQ at 0.15ng/ml for both).


Assuntos
Aminorex/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Levamisol/urina , Adulto , Animais , Cocaína/urina , Cães , Contaminação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Transtornos Relacionados ao Uso de Substâncias/urina
18.
J Vet Pharmacol Ther ; 32(2): 160-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19290946

RESUMO

Beginning in 2004, the horseracing industry experienced an epidemic of drug positives for the amphetamine-like drug aminorex. Investigation of the therapeutic treatment of the horses called positive for this drug suggested that its source was from the administration of the anthelmintic levamisole. This study examines the urine concentrations of aminorex as a function of time following administration of synthetic, racemic aminorex. Confirmation of the presence of aminorex in urine samples from the horses known to be treated with levamisole is also presented as are data concerning the concentrations of aminorex in positives called from the field and the corresponding concentrations of levamisole found in the same samples. Furthermore, this study illustrates that the chiral isomer distribution of aminorex found in samples from the field is significantly different from that arising from the administration of synthetic, racemic aminorex and is similar to that observed from aminorex arising from levamisole administration. An examination of the chiral isomer distribution of aminorex and a determination of the presence of levamisole in a sample may be used to assess the source of an aminorex positive, distinguishing it from an intentional synthetic, racemic aminorex administration. The role of levamisole in aminorex formation is also discussed.


Assuntos
Aminorex/urina , Antinematódeos/urina , Doping nos Esportes , Cavalos/urina , Levamisol/urina , Administração Oral , Aminorex/química , Animais , Antinematódeos/administração & dosagem , Antinematódeos/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas/veterinária , Isomerismo , Levamisol/administração & dosagem , Levamisol/metabolismo , Pennsylvania
19.
Anal Chim Acta ; 638(1): 58-68, 2009 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-19298880

RESUMO

Administration studies of levamisole in horses were carried out using two different levamisole preparations, namely, levamisole hydrochloride oral bolus and levamisole phosphate injectable solution. These preparations were analysed in detail for the presence of aminorex-like impurities. Both levamisole preparations were found to contain 1-(2-mercaptoethyl)-4-phenyl-2-imidazolidinone (I) and 4-phenyl-2-imidazolidinone (II) as degradation impurities, but neither aminorex nor rexamino was detected in these preparations. After the administration of these preparations to horses, aminorex, rexamino, in addition to levamisole and compound II, were detected in post-administration urine and plasma samples, among which compound II was found to have the longest detection time. Administration study of compound II was then performed on another horse to investigate whether it could be a metabolic precursor of aminorex and/or rexamino. However, no aminorex and rexamino was detected in the post-administration samples, suggesting that compound II was not a metabolic precursor of aminorex or rexamino. A metabolite (III) of compound II, tentatively identified to be a hydrolysis product of compound II, was observed instead. It has been established unequivocally that the normal use of levamisole products in horses can lead to the presence of aminorex, rexamino and 4-phenyl-2-imidazolidinone (II) in their urine and blood samples. As compound II has the longest detection time, the detection of aminorex (and in some cases rexamino) in some of the official samples from racehorses can be ascribed to the use of levamisole products as long as compound II is also present as a marker. These findings should be of direct relevance to the investigation of some of the cases of aminorex detection in official doping control samples from racehorses.


Assuntos
Aminorex/análise , Cavalos/metabolismo , Levamisol/metabolismo , Compostos de Estanho/química , Administração Oral , Aminorex/sangue , Aminorex/urina , Animais , Cromatografia Líquida , Doping nos Esportes , Cromatografia Gasosa-Espectrometria de Massas , Levamisol/administração & dosagem , Levamisol/análise , Estereoisomerismo , Espectrometria de Massas em Tandem
20.
Am J Vet Res ; 69(5): 675-81, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18447801

RESUMO

OBJECTIVE: To investigate the pharmacokinetics and behavioral effects of aminorex administered IV and PO in horses. ANIMALS: 7 Thoroughbreds. PROCEDURES: In a cross-over design, aminorex (0.03 mg/kg) was administered IV or PO. Plasma and urinary aminorex concentrations were determined via liquid chromatography- mass spectrometry. RESULTS: Decrease of aminorex from plasma following IV administration was described by a 3-compartment pharmacokinetic model. Median (range) values of alpha, beta, and gamma half-lives were 0.04 (0.01 to 0.28), 2.30 (1.23 to 3.09), and 18.82 (8.13 to 46.64) hours, respectively. Total body and renal clearance, the area under the plasma time curve, and initial volume of distribution were 37.26 (28.61 to 56.24) mL x min/kg, 1.25 (0.85 to 2.05) mL x min/kg, 13.39 (8.82 to 17.37) ng x h/mL, and 1.44 (0.10 to 3.64) L/kg, respectively. Oral administration was described by a 2-compartment model with first-order absorption, elimination from the central compartment, and distribution into peripheral compartments. The absorption half-life was 0.29 (0.12 to 1.07) hours, whereas the beta and gamma elimination phases were 1.93 (1.01 to 3.17) and 23.57 (15.16 to 47.45) hours, respectively. The area under the curve for PO administration was 10.38 (4.85 to 13.40) ng.h/mL and the fractional absorption was 81.8% (33.8% to 86.9%). CONCLUSIONS AND CLINICAL RELEVANCE: Aminorex administered IV had a large volume of distribution, initial rapid decrease, and an extended terminal elimination. Following PO administration, there was rapid absorption, rapid initial decrease, and an extended terminal elimination. At a dose of 0.03 mg/kg, the only effects detected were transient and central in origin and were observed only following IV administration.


Assuntos
Aminorex/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cavalos/metabolismo , Administração Oral , Aminorex/sangue , Aminorex/farmacocinética , Aminorex/urina , Animais , Área Sob a Curva , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/urina , Estudos Cross-Over , Feminino , Meia-Vida , Infusões Intravenosas , Masculino , Distribuição Aleatória
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