RESUMEN
Amphetamine (AMP) and methamphetamine (METH) use is increasing globally. Illegal AMP is generally a racemic mixture, whereas AMP-containing attention-deficit hyperactivity disorder drugs prescribed in Iceland consist of S-AMP. AMP is also a main metabolite of interest after METH intake. Distinguishing between legal and illegal AMP intake is vital in forensic toxicology. A chiral UPLC-MS-MS method was used to determine the enantiomeric profile of AMP and METH in circulation in Iceland by analysing blood samples from drivers suspected of driving under the influence of drugs (DUID) and seized drug samples from 2021 and 2022. All seized AMP samples (n = 48) were racemic, whereas all but one seized METH sample (n = 26) were enantiopure. Surprisingly, a large portion of the enantiopure METH samples was R-METH. DUID blood samples positive for AMP (n = 564) had a median blood concentration of 180 ng/mL (range 20-2770 ng/mL) and a median enantiomeric fraction (EFR) of 0.54 (range 0-0.73), whereas samples positive for METH (n = 236) had a median blood concentration of 185 ng/mL (range 20-2300 ng/mL) and a median EFR of 0.23 (range 0-1). The findings of this study show a significantly lower blood concentration in drivers with only S-AMP detected compared with when the R-isomer is also detected. No significant difference in blood concentration was detected between the sample groups containing S-METH, R-METH or both enantiomers. The occurrence of R-METH in both seized drug samples and DUID cases indicates a change in drug supply and a need for better scientific knowledge on R-METH abuse.
Asunto(s)
Anfetaminas , Metanfetamina , Detección de Abuso de Sustancias , Espectrometría de Masas en Tándem , Humanos , Islandia , Estereoisomerismo , Metanfetamina/sangre , Detección de Abuso de Sustancias/métodos , Anfetaminas/sangre , Conducir bajo la Influencia , Conducción de Automóvil , Toxicología Forense , Drogas Ilícitas/sangre , Anfetamina/sangre , Estimulantes del Sistema Nervioso Central/sangreRESUMEN
Illegal amphetamine is usually composed of a racemic mixture of the two enantiomers (S)- and (R)-amphetamine. However, when amphetamine is used in medical treatment, the more potent (S)-amphetamine enantiomer is used. Enantiomer-specific analysis of (S)- and (R)-amphetamine is therefore used to separate legal medical use from illegal recreational use. The aim of the present study was to describe our experience with enantiomer-specific analysis of amphetamine in urine and oral fluid, as well as blood, and examine whether the distribution of the two enantiomers seems to be the same in different matrices. We investigated 1,722 urine samples and 1,977 oral fluid samples from prison inmates, and 652 blood samples from suspected drugged drivers, where prescription of amphetamine was reported. Analyses were performed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS). The enantiomer separation was achieved by using a chiral column, and results from the method validation are reported. Samples containing <60% (S)-amphetamine were interpreted as representing illegal use of amphetamine. The distribution of the two enantiomers was compared between different matrices. In urine and oral fluid, the mean amount of (S)-amphetamine was 45.2 and 43.7%, respectively, while in blood, the mean amount of (S)-amphetamine was 45.8%. There was no statistically significant difference in the amount of (S)-amphetamine between urine and oral fluid samples and between urine and blood samples, but the difference was significant in blood compared to oral fluid samples (P < 0.001). Comparison of urine and oral fluid between similar populations indicated that enantiomers of amphetamine can be interpreted in the same way, although marginally higher amounts of (R)-amphetamine may occur in oral fluid. Oral fluid, having several advantages, especially during collection, could be a preferred matrix in testing for illegal amphetamine intake in users of medical amphetamine.
Asunto(s)
Anfetamina , Saliva , Detección de Abuso de Sustancias , Espectrometría de Masas en Tándem , Humanos , Anfetamina/orina , Anfetamina/sangre , Anfetamina/análisis , Saliva/química , Estereoisomerismo , Detección de Abuso de Sustancias/métodos , Cromatografía Líquida de Alta Presión , Estimulantes del Sistema Nervioso Central/orina , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/análisisRESUMEN
The amphetamine molecule contains a chiral center and its enantiomers exhibit differences in pharmacological effects, with the S-enantiomer mediating most of the central nervous system stimulating activity. The majority of prescribed amphetamine consists of the pure S-enantiomer, but therapeutic formulations containing the R-enantiomer in various proportions are also available. Illegal amphetamine remains available mainly as a racemic mixture of the R- and S-enantiomers. To distinguish between legal and illegal consumption of amphetamine a method for enantiomeric separation and quantification of R/S-amphetamine in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was performed by a semi-automated liquid-liquid extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO2 and 0.1% ammonium hydroxide in 2-propanol/methanol (50/50, v/v). The injection volume was 2 µL and run time was 4 minutes. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 12.5-1,000 nM for each analyte. The between-assay relative standard deviations were in the range of 1.3-3.0%. Recovery was 73% and matrix effects ranged from 95 to 100% when corrected with internal standard. After development and validation, the method has been successfully implemented in our laboratory for both separation and quantification of R/S-amphetamine and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples.
Asunto(s)
Anfetamina/análisis , Estimulantes del Sistema Nervioso Central/análisis , Cromatografía con Fluido Supercrítico/métodos , Espectrometría de Masas en Tándem/métodos , Anfetamina/sangre , Anfetamina/química , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/química , Cromatografía Líquida de Alta Presión , Humanos , Extracción Líquido-Líquido , Reproducibilidad de los Resultados , EstereoisomerismoRESUMEN
We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.
Asunto(s)
Anfetamina/envenenamiento , Drogas de Diseño/envenenamiento , Masturbación , Pirrolidinas/envenenamiento , Baño de Vapor/efectos adversos , Trastornos Relacionados con Sustancias/complicaciones , Anfetamina/sangre , Benzodiazepinas/sangre , Buprenorfina/sangre , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas/sangre , Insuficiencia RespiratoriaRESUMEN
Objective: In the U.S. â¼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.
Asunto(s)
Anfetamina/farmacocinética , Administración Oral , Anfetamina/administración & dosificación , Anfetamina/efectos adversos , Anfetamina/sangre , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/farmacocinética , Preescolar , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/farmacocinética , Femenino , Humanos , MasculinoRESUMEN
Storage and quantitative analysis of small volumes of biofluids are challenging, especially when low concentrations of analytes are to be detected in the presence of complex matrices. In this study, we describe an integrated thread-based approach for stabilizing small blood volumes in the dry-state at room temperature, while also offering direct analysis capabilities via thread spray mass spectrometry. The analytical merits of this novel microsampling platform was demonstrated via the direct analysis of diazepam and cocaine in dried blood samples stored for 42 days. In-situ in-capillary blood processing from hydrophobic threads enabled limits of detection as low as parts-per-quadrillion to be reached. We validated this ultra-sensitivity by analyzing small tissue-like residues collected after pushing a thread through the sample once. The implications of this sample collection, storage, and analysis platform can be extensive with direct applications in forensics and clinical studies.
Asunto(s)
Fibra de Algodón , Pruebas con Sangre Seca/métodos , Extracción en Fase Sólida/métodos , Anfetamina/sangre , Cocaína/análogos & derivados , Cocaína/sangre , Diazepam/sangre , Pruebas con Sangre Seca/instrumentación , Gossypium , Humanos , Límite de Detección , Espectrometría de Masas/métodos , Metanfetamina/sangre , Sefarosa/química , Extracción en Fase Sólida/instrumentación , Manejo de EspecímenesRESUMEN
In this report, a pediatric case of bowel obstruction with sepsis complicated by methamphetamine toxicity is described. The decedent, an eleven-year-old female with a clinical history of pica, was found unresponsive in her home and pronounced dead following unsuccessful resuscitative efforts. Radiologic imaging showed multiple radio-opaque foreign objects in the stomach and bowel. Autopsy revealed a green leafy substance, coins and other metallic items, folded paper, and plastic in her stomach and bowels. Postmortem iliac blood and urine tested positive for amphetamine and methamphetamine. While the decedent's medical history and autopsy findings provided evidence consistent with bowel obstruction with sepsis due to the ingestion of foreign materials, the high methamphetamine concentration was suggestive of concurrent methamphetamine toxicity. Unique complications associated with this case include the phenomenon that methamphetamine toxicity and bowel obstruction can present similarly in children and the reported opinion that accidental drug ingestion is uncommon in children over the age of five. This case emphasizes that the age range for suspected accidental drug ingestion should be expanded for those with pica, as these patients, despite being older, may not be able to differentiate between what they should and should not ingest. Furthermore, when treating a pediatric patient with pica that appears to present with bowel obstruction, unintentional drug ingestion should also be considered, particularly if there is a suspicion that the child lives in a household where drugs are abused, given the prospect that drug toxicity can present similarly.
Asunto(s)
Estimulantes del Sistema Nervioso Central/efectos adversos , Obstrucción Intestinal/etiología , Metanfetamina/efectos adversos , Pica/complicaciones , Sepsis/etiología , Anfetamina/sangre , Anfetamina/orina , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/orina , Niño , Colon Sigmoide/diagnóstico por imagen , Sobredosis de Droga , Femenino , Cuerpos Extraños/diagnóstico por imagen , Humanos , Obstrucción Intestinal/diagnóstico por imagen , Metanfetamina/sangre , Metanfetamina/orina , Sepsis/patología , Estómago/diagnóstico por imagenRESUMEN
A novel mass spectrometry detection technique based on a multi-period and multi- experiment (MRM-EPI-MRM3) with library matching in a single run for fast and rapid screening and identification of amphetamine type stimulants (ATS) related drugs in whole blood, urine and dried blood stain was developed and validated. The ATS-related drugs analyzed in this study include ephedrine, pseudoephedrine, amphetamine, methamphetamine, MDMA (3,4-Methylenedioxymethamphetamine), MDA (3,4-Methylenedioxyamphetamine), MDEA (3,4-Methylenedioxy-N-ethylamphetamine) and phentermine. The relative standard deviation for inter and intraday was less than 15% while recoveries ranged from 80% to 120% for all three matrices, i.e., whole blood, urine and dried blood stain. All compounds gave library matching percentage of more than 85% based on the purity. This method was proven to be simple and robust, and provide high confident results complemented with library matching confirmation.
Asunto(s)
Anfetamina , Manchas de Sangre , Estimulantes del Sistema Nervioso Central , Toxicología Forense/métodos , Detección de Abuso de Sustancias/métodos , Anfetamina/sangre , Anfetamina/orina , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/orina , Cromatografía Liquida , Toxicología Forense/instrumentación , Humanos , Límite de Detección , Reproducibilidad de los Resultados , Detección de Abuso de Sustancias/instrumentación , Espectrometría de Masas en TándemRESUMEN
Structural analogs of classic drugs, also called designer drugs, are a booming market due to the easy accessibility on the internet and their legal status. One of those 'legal highs' is an analog of phencyclidine, namely 3-methoxyphencyclidine (3-MeO-PCP). Very few fatalities have been reported where 3-MeO-PCP contributed to the death of an individual. We present the first fatal case in the Netherlands and one of the few worldwide. Postmortem biological samples and the presumed abused unknown substance, sold as ant poison, were obtained. 3-MeO-PCP was detected, and the resulting concentration was 152⯵g/l in whole blood. The presumed taken unknown sample was identified as 3-MeO-PCP and thus linked to the victim. The cause of death was a combination of 3-MeO-PCP, amphetamine, and alcohol. Improved diagnostic skills are necessary to face these emerging novel psychoactive substances also in light of public health and social risks.
Asunto(s)
Drogas de Diseño/envenenamiento , Fenciclidina/análogos & derivados , Psicotrópicos/envenenamiento , Adulto , Anfetamina/sangre , Nivel de Alcohol en Sangre , Cromatografía Liquida , Drogas de Diseño/análisis , Humanos , Masculino , Espectrometría de Masas/métodos , Países Bajos , Fenciclidina/sangre , Fenciclidina/envenenamiento , Psicotrópicos/sangre , Trastornos Relacionados con Sustancias/sangreRESUMEN
Brain tissue may serve as a useful supplement to blood in postmortem investigations. However, reference concentrations for central stimulant drugs are scarce in brain tissue. This study involves some frequently used stimulants: amphetamine, cocaine, ephedrine, MDMA and methylphenidate. We present concentrations from brain and blood and brain-blood ratios of the analytes from autopsies. The cases were grouped according to the cause of death: A: The compound solely caused a fatal intoxication. B: The compound contributed to a fatal outcome in combination with other drugs, alcohol or disease. C: The compound was not related to the cause of death. Analyses were carried out using solid-phase extraction and ultra high-performance liquid chromatography. Paired brain and femoral blood concentrations from 133 cases were analysed. Positive correlations were observed for all analytes with correlation coefficients ranging from 0.58 to 0.95. The following median brain-blood ratios were obtained: cocaine 2.0 (range 0.20-7.0), amphetamine 3.2 (range 1.5-4.5), ephedrine 2.3 (range 1.1-6.2), MDMA 3.9 (range 0.92-5.1) and methylphenidate 2.4 (0.92-4.6). The concentrations in femoral blood generally agreed with the literature for all compounds. The metabolite of cocaine, benzoylecgonine, was also quantified in brain and blood from 60 cases, and the median brain-blood ratio was 0.66 with 10-90 percentiles of 0.39-1.27. The results of this study can aid the toxicological investigation in determining the cause of death.
Asunto(s)
Anfetamina/sangre , Cocaína/sangre , Toxicología Forense/métodos , Sustancia Gris/química , Metilfenidato/sangre , N-Metil-3,4-metilenodioxianfetamina/sangre , Autopsia , Química Encefálica , Calibración , Toxicología Forense/instrumentación , Humanos , Cambios Post Mortem , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
The differentiation between single methamphetamine consumption and co-consumption with amphetamine is difficult, however possible by enantioselective analysis due to different preferred synthesis pathways of both substances. We quantified (R)-(-) and (S)-(+)-enantiomers of methamphetamine and amphetamine by a fast liquid chromatographic tandem-mass spectrometric method using a Lux® 3-µm AMP 150 × 3.0 mm analytical column after simple protein precipitation with methanol. Method validation for quantitative detection showed limits of quantification < 5 ng/mL, linearity in a range between 5 and 300 ng/mL and bias and imprecision data < 15%. Overall, 134 plasma samples of police cases from the German regions of Franconia and Northrhine-Westphalia were analyzed for the enantiomers of methamphetamine and amphetamine. In 28 cases, the intake of racemic illicit amphetamine could be demonstrated; (R)-(-) / (S)-(+)-amphetamine concentration ratios in these cases were between 1.38 and 4.50 with most of the ratios being < 2.0. These ratios were compared to a subgroup of 25 consumers with a co-consumption of (S)-(+)-methamphetamine and racemic amphetamine detected by the qualitative proof of (R)-(-)-amphetamine but also by (R)-(-) / (S)-(+)-amphetamine concentration ratios (< 1 in 11 of 25 cases). Within our collective of 106 plasma samples after methamphetamine use, 25 samples showed co-consumption with amphetamine which shows that co-consumption of both stimulants is not a rare scenario. Furthermore, we could show that if non-stereoselective methods are used and the concentration ratio of total methamphetamine/total amphetamine is determined, a reliable estimation of co-consumption is not possible.
Asunto(s)
Trastornos Relacionados con Anfetaminas/diagnóstico , Anfetamina/química , Estimulantes del Sistema Nervioso Central/química , Metanfetamina/química , Anfetamina/sangre , Estimulantes del Sistema Nervioso Central/sangre , Cromatografía Liquida , Humanos , Metanfetamina/sangre , Estereoisomerismo , Detección de Abuso de Sustancias , Espectrometría de Masas en TándemRESUMEN
Fluoride is a common stabilizing agent in forensic toxicology to avoid the frequent problem of degradation of drugs in blood samples especially described for cocaine. In cases only samples with addition of fluoride are available, it is a crucial question if also concentrations of common drugs other than cocaine (amphetamines, opiates and cannabinoids) are affected by fluoride. So far, there are only rare literature data available on discrepant results especially for Δ9-tetrahydrocannabinol (THC). In this study, comparative analysis of positive tested paired routine plasma/serum samples (n = 375), collected at the same time point (one device with and one without fluoride), was carried out with special focus on cannabinoids. Samples were measured with validated routine liquid chromatography-tandem mass spectrometry methods for THC, 11-hydroxy-THC (THC-OH), 11-nor-9-carboxy-THC (THC-COOH), cocaine, benzoylecgonine, ecgonine methyl ester, morphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxyethylamphetamine, and results were statistically evaluated. Beside the expected stabilization effect on cocaine and the consequently reduced concentration of ecgonine methyl ester in fluoride samples, benzoylecgonine was elevated compared to respective samples without fluoride. Most importantly, new findings were significantly reduced mean concentrations of THC (- 17%), THC-OH (- 17%), and THC-COOH (- 22%) in fluoride samples. Mean amphetamine concentration was significantly higher in samples with the additive (+ 6%). For the other amphetamine type of drugs as well as for morphine and codeine, no significant differences could be seen. Whenever specified thresholds have been set, such as in most European countries, the use of different blood sample systems may result in a motorist being differently charged or prosecuted. The findings will support forensic toxicologists at the interpretation of results derived from fluoride-stabilized blood samples.
Asunto(s)
Excipientes/química , Fluoruros/química , Drogas Ilícitas/sangre , Manejo de Especímenes , Anfetamina/sangre , Cromatografía Liquida , Dronabinol/sangre , Toxicología Forense , Humanos , Espectrometría de Masas en TándemRESUMEN
Methamphetamine can be synthesized either enantiopure or in its racemic form. We separated (R)- and (S)-enantiomers of methamphetamine and amphetamine by a fast LC-MS/MS-method using a Lux® 3µm AMP 150×3.0mm analytical column after simple protein precipitation with methanol. Sufficient resolution could be achieved. Method validation for qualitative detection showed limits of quantification <5ng/mL while only little (maximum 14.5%) ion suppression could be shown. Stability in the processed sample could be achieved using isotopically labelled internal standards. Plasma samples of police cases from the german regions of Franconia and Northrhine revealed that in the majority of 106 tested samples (>99%) only (S)-methamphetamine was detected which leads to the conclusion that, in Germany, predominantly enantiopure (S)-methamphetamine is consumed which is synthesized via (1R,2S)-ephedrine or (1S,2S)-pseudoephedrine. However, racemic methamphetamine seems also to be on the market.
Asunto(s)
Anfetamina/sangre , Anfetamina/síntesis química , Metanfetamina/sangre , Metanfetamina/síntesis química , Cromatografía Liquida , Humanos , Espectrometría de Masas , EstereoisomerismoRESUMEN
Amphetamine, methamphetamine, phentermine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxy-N-ethylamphetamine (MDEA) are the most popular amphetamine-type stimulants. The use of these substances is a serious societal problem worldwide. In this study, a method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) with simple and rapid liquid-liquid extraction (LLE) and derivatization was developed and validated for the simultaneous determination of the six aforementioned amphetamine derivatives in blood and urine. The detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The most important advantage of the method is the minimal sample volume (as low as 200µL) required for the extraction procedure. The validation parameters, i.e., the recovery (90.5-104%), inter-day accuracy (94.2-109.1%) and precision (0.5-5.8%), showed the repeatability and sensitivity of the method for both matrices and indicated that the proposed procedure fulfils internationally established acceptance criteria for bioanalytical methods The procedure was successfully applied to the analysis of real blood and urine samples examined in 22 forensic toxicological cases. To the best of our knowledge, this is the first work presenting the use of GC-MS/MS for the determination of amphetamine-type stimulants in blood and urine. In view of the low limits of detection (0.09-0.81ng/mL), limits of quantification (0.26-2.4ng/mL), and high selectivity, the procedure can be applied for drug monitoring in both fatal and non-fatal intoxication cases in routine toxicology analysis.
Asunto(s)
Anfetamina/sangre , Anfetamina/orina , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Límite de Detección , Extracción Líquido-Líquido/métodos , Reproducibilidad de los Resultados , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
PURPOSE: A new amphetamine extended-release liquid formulation (AMP XR-OS), intended for the treatment of attention-deficit/hyperactivity disorder, has been developed. This study was performed to determine if administration with food affected the rate of absorption or bioavailability of AMP XR-OS. The formulation was also compared with an equivalent dose of an extended-release mixed amphetamine salts reference product (30 mg) under fed conditions. METHODS: Thirty adult volunteers participated in this single-dose, open-label, randomized, 3-period, 3-treatment crossover study. Each participant received a single 15-mL dose of AMP XR-OS (equivalent to 30 mg of the reference drug) under fasted conditions, a single 15-mL dose of AMP XR-OS under fed conditions, and a single dose of the reference drug under fed conditions. A 7-day washout separated the 3 treatment periods. Blood samples were collected at predetermined time points and analyzed for d- and l-amphetamine. Pharmacokinetic parameters reported are AUC0-5, AUC0-last, AUC5-last, and AUC0-∞; Cmax; elimination t1/2; and Tmax. The geometric mean ratios and 90% CIs of Cmax, AUC0-last, and AUC0-∞were determined for the comparison of AMP XR-OS fed and fasted, and Cmax, AUC0-5, AUC5-last, and AUC0-∞ were calculated for AMP XR-OS compared with the reference drug under fed conditions. Safety was also assessed. FINDINGS: Twenty-nine subjects completed the study. Subjects were mostly male, white, and of Hispanic/Latino ethnicity with a mean age of 35.83 years and a mean BMI of 25.36kg/m2. The 90% CIs of Cmax, AUC0-last, and AUC0-∞ for AMP XR-OS fasted versus fed were within the accepted 80% to 125% range, indicating lack of a food effect. In the comparison of AMP XR-OS fed versus the reference product, Cmax, AUC5-last, and AUC0-∞ were within the range to establish bioequivalence; however, AUC0-5 was significantly higher for AMP XR-OS compared with that of the reference drug. This difference between products was likely due to the known delay of Tmax and decreased exposure when the extended-release mixed amphetamine salts reference product is administered with food. A total of 36 mild or moderate adverse events were reported; 1 subject withdrew due to an adverse event, and no deaths occurred. These adverse events were consistent with the known pharmacodynamic effects of amphetamine. IMPLICATIONS: The absence of a food effect may allow for AMP XR-OS to be administered with or without a meal.
Asunto(s)
Anfetamina/farmacocinética , Preparaciones de Acción Retardada/farmacocinética , Administración Oral , Adulto , Anciano , Anfetamina/efectos adversos , Anfetamina/sangre , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Preparaciones de Acción Retardada/efectos adversos , Ayuno/metabolismo , Femenino , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Adulto JovenRESUMEN
A detailed description is given of the development and validation of a fully automated in-line solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method capable of detecting 90 central-stimulating new psychoactive substances (NPS) and 5 conventional amphetamine-type stimulants (amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA), methamphetamine) in serum. The aim was to apply the validated method to forensic samples. The preparation of 150µL of serum was performed by an Instrument Top Sample Preparation (ITSP)-SPE with mixed mode cation exchanger cartridges. The extracts were directly injected into an LC-MS/MS system, using a biphenyl column and gradient elution with 2mM ammonium formate/0.1% formic acid and acetonitrile/0.1% formic acid as mobile phases. The chromatographic run time amounts to 9.3min (including re-equilibration). The total cycle time is 11min, due to the interlacing between sample preparation and analysis. The method was fully validated using 69 NPS and five conventional amphetamine-type stimulants, according to the guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh). The guidelines were fully achieved for 62 analytes (with a limit of detection (LOD) between 0.2 and 4µg/L), whilst full validation was not feasible for the remaining 12 analytes. For the fully validated analytes, the method achieved linearity in the 5µg/L (lower limit of quantification, LLOQ) to 250µg/L range (coefficients of determination>0.99). Recoveries for 69 of these compounds were greater than 50%, with relative standard deviations≤15%. The validated method was then tested for its capability in detecting a further 21 NPS, thus totalling 95 tested substances. An LOD between 0.4 and 1.6µg/L was obtained for these 21 additional qualitatively-measured substances. The method was subsequently successfully applied to 28 specimens from routine forensic case work, of which 7 samples were determined to be positive for NPS consumption.
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Psicotrópicos/sangre , Detección de Abuso de Sustancias/métodos , Adulto , Anfetamina/sangre , Cromatografía Liquida/métodos , Cocaína/sangre , Humanos , Ketamina/sangre , Límite de Detección , Modelos Lineales , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
Paper spray tandem mass spectrometry is used to identify and quantify eight individual amphetamines in whole blood in 1.3 min. The method has been optimized and fully validated according to forensic toxicology guidelines, for the quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-N-methylamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), and 4-fluoroamphetamine (4-FA). Additionally, a new concept of intrinsic and application-based selectivity is discussed, featuring increased confidence in the power to discriminate the amphetamines from other chemically similar compounds when applying an ambient mass spectrometric method without chromatographic separation. Accuracy was within ±15% and average precision was better than 15%, and better than 20% at the LLOQ. Detection limits between 15 and 50 ng/mL were obtained using only 12 µL of whole blood. Graphical abstract á .
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Anfetamina/sangre , Estimulantes del Sistema Nervioso Central/sangre , Toxicología Forense/métodos , Espectrometría de Masas/métodos , Anfetamina/análisis , Estimulantes del Sistema Nervioso Central/análisis , Humanos , Límite de Detección , Papel , Reproducibilidad de los Resultados , Detección de Abuso de Sustancias/métodosRESUMEN
PURPOSE: There is a strong association between attention-deficit/hyperactivity disorder (ADHD) and alcohol abuse, yet no studies have systematically assessed the effect of alcohol on the pharmacokinetics of psychostimulants such as amphetamine (AMP) in vivo. This study evaluated the effects of alcohol on the rate and extent of absorption of Adzenys™ XR-ODT*, a new extended-release orally disintegrating AMP tablet (AMP XR-ODT) for ADHD. METHODS: A Phase I single-dose, open-label study was conducted in 32 healthy adults. Participants were split into 2 cohorts, allowing for close monitoring of safety profile and tolerability, and were randomized 1:1:1:1 to receive treatment in 1 of 4 sequences. Each treatment included the administration of a single 18.8-mg dose of AMP XR-ODT, followed by 240 mL of deionized water or 4%, 20%, or 40% ethanol. Blood samples were collected at prespecified time points. The pharmacokinetic profiles of d- and l-AMP were comparable across treatment groups. FINDINGS: There was no change in the extent of absorption for d- or l-AMP with alcohol coingestion and no dose dumping of the extended-release portion of the formulation. The 90% CIs for the geometric mean ratios (4%, 20%, and 40% ethanol versus water) for Cmax and systemic exposure (AUC0-5, AUClast, and AUC0-∞) were within 80% to 125%. Adverse events were mild to moderate and were consistent with the known adverse event profile for AMP XR-ODT or alcohol. IMPLICATIONS: Varying concentrations of alcohol (4%-40%) did not significantly alter the pharmacokinetic profile of AMP XR-ODT. These findings are relevant to clinicians who have concerns about alcohol use and/or abuse when treating ADHD.
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Anfetamina/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Etanol/farmacología , Administración Oral , Adulto , Anfetamina/sangre , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Estimulantes del Sistema Nervioso Central/sangre , Estudios Cruzados , Preparaciones de Acción Retardada/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Comprimidos , Adulto JovenRESUMEN
Medico-legal experts are increasingly enlisted to assess the methamphetamine and amphetamine serum concentrations after a criminal offense. However, since criminal users rarely provide useful information to medico-legal experts regarding the substances abused, when the substance(s) was/were used, dose of ingestion tools are needed to interpret the analytical data, which can be used as objective evidence in such cases. A comparative series of methamphetamine and amphetamine serum concentrations were used to analyze the frequency of concentrations, to determine methamphetamine/amphetamine concentration ratios, and prove them as a tool to distinguish pure methamphetamine from mixed amphetamine/methamphetamine ingestion. Additionally, two cases of survived accidental methamphetamine intoxication, resulting from ingestion smuggling which was longitudinally monitored, and pharmacokinetic parameters were assessed. In a series of 628 samples where the most frequent concentration of methamphetamine exceeded the therapeutic level, there was a strong correlation suggesting pure methamphetamine consumption, when the ratios of methamphetamine/amphetamine concentrations were within the range between 3 and 10. In the two cases of methamphetamine bodypacking, the relevant serum concentrations of methamphetamine and amphetamine, which could be measured up to 9 days after ingestion, indicated a decrease of the methamphetamine/amphetamine ratios in an exponential manner. However, the ratios were not always within the range between 3 and 10. Lastly, the course of the serum concentrations suggested an increase of the apparent elimination half-life of methamphetamine. In terms of the objective evidence required in criminal law, calculating methamphetamine/amphetamine concentration ratio is not a suitable to means to distinguish pure methamphetamine intake and that of mixed amphetamine/methamphetamine abuse in an individual case. Instead, methamphetamine high serum concentrations and the possible increase in apparent elimination half-life suggest that an extended detection period may be used to distinguish between "illicit use" as compared to "therapeutic use" of methamphetamine.
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Anfetamina/sangre , Metanfetamina/sangre , Narcóticos/sangre , Adulto , Anfetamina/farmacocinética , Transporte Intracorporal de Contrabando , Conducir bajo la Influencia , Sobredosis de Droga , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Masculino , Metanfetamina/farmacocinética , Persona de Mediana Edad , Narcóticos/farmacocinética , Detección de Abuso de SustanciasRESUMEN
OBJECTIVE: Older drivers are somewhat more likely to be involved in car crashes than middle-aged drivers but less likely to be involved than younger drivers. This study aimed to assess the extent of drug use in older suspected drunk and drugged drivers, with respect to which drugs were detected and at which concentrations. METHODS: Blood samples from older suspected drunk and drugged drivers taken between February 1, 2012, and May 22, 2013, were identified from the database at the Norwegian Institute of Public Health and were retrospectively analyzed for a broad repertoire of drugs relevant for impairment. The prevalence of different drugs among the suspected drunk and drugged drivers was studied. Regarding drug concentrations, the findings in older drivers (>65 years) were compared to a reference group of apprehended drivers aged 20-40 years. RESULTS: Four hundred and ten older suspected drunk and drugged drivers were included. Any drug (including ethanol) was detected in 92% of blood samples, and ethanol was detected in 81%. Benzodiazepines were found in 15% of the older drivers and z-hypnotics (zopiclone or zolpidem) were detected in 13%. The most frequent single legal drugs found in blood samples taken from older impaired drivers were zopiclone (9.8%) and diazepam (9.3%). Regarding drug combinations, older drivers used a mean number of 1.4 drugs, and 20% of ethanol-positive cases showed at least one other drug. High drug concentrations of clonazepam and diazepam were more frequently seen in the younger group. CONCLUSIONS: This study showed that drugs were detected in the vast majority of older drivers suspected for drunk or drugged driving. Ethanol was the most frequent drug detected, followed by zopiclone and diazepam. Older drivers combine drugs to a lesser degree than younger drivers, but their combination of ethanol and other drugs represents a considerable traffic risk. Lower concentrations of benzodiazepines are seen in older compared to younger drivers.