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1.
MMWR Morb Mortal Wkly Rep ; 69(5): 125-129, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32027630

RESUMO

Increased prevalence of illicitly manufactured fentanyl and fentanyl analogs has contributed substantially to overdose deaths in the United States (1-3). On October 26, 2015, CDC issued a Health Advisory regarding rapid increases in deaths involving fentanyl. This CDC Health Advisory has been updated twice to address increases in fentanyl and fentanyl analog overdoses and their co-occurrence with nonopioids (4). Deaths involving carfentanil, an analog reportedly 10,000 times more potent than morphine and 100 times more potent than fentanyl, were first reported in Florida, Michigan, and Ohio in 2016 and described in an August 2016 CDC Health Advisory (1,5). Carfentanil is used to rapidly immobilize large animals in veterinary medicine and has no U.S. approved therapeutic use in humans. Carfentanil's street price per dose is likely lower than that of heroin. During 2016 and 2017, an outbreak of carfentanil-involved fatal overdoses in Florida emerged, and the Medical Examiner jurisdiction serving Sarasota, Manatee, and DeSoto counties (the Sarasota area) was the outbreak epicenter. This report describes toxicology profiles, sociodemographic information, and geographic distributions of carfentanil-involved fatal overdoses (carfentanil deaths) in the Sarasota area compared with those in the rest of Florida (i.e., all Florida counties excluding Sarasota area) from January 2016 to December 2017. The Sarasota area accounted for 19.0% of 1,181 statewide carfentanil deaths that occurred during this time and experienced a peak in carfentanil deaths preceding the larger Florida outbreak. The report of a single carfentanil death from August to December 2017 (compared with 73 reported deaths during the same period in 2016) appeared to mark the end of the outbreak in the area. The threat of such rapid, intense fatal overdose outbreaks highlights the need for accelerated reporting, reliable data sharing systems, and novel proactive surveillance to support targeted prevention and response efforts by public health and safety organizations (6).


Assuntos
Surtos de Doenças , Overdose de Drogas/mortalidade , Fentanila/análogos & derivados , Adulto , Feminino , Fentanila/envenenamento , Florida/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade
2.
Life Sci ; 246: 117400, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32032645

RESUMO

AIMS: Comparative sub-acute toxicity, including tolerance and dependence potential of fentanyl and its three novel and potent analogues was determined in mice. MAIN METHODS: Comparative sub-acute (21 d, intraperitoneal; 1/10 LD50) toxicity of fentanyl and its three novel analogues viz., N-(1-(2-phenoxyethyl)-4-piperidinyl) propionanilide (2), N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6) was determined in mice. Animals were observed for additional seven days to assess the recovery. The brain, liver and kidney toxicity was assessed on the basis of various biochemical, oxidative, histological, and neuroadaptive markers. The expression levels of key neuronal markers associated with drug tolerance and dependence were investigated by western blot and immunohistochemistry. KEY FINDINGS: Fentanyl and its analogues caused abnormal levels of liver and kidney specific biomarkers in plasma. Brain malondialdehyde (MDA) levels were raised by all the treatments and kidney MDA level by analogue 6 (21 d). Reduced glutathione levels in brain, liver, and kidney were diminished by all the treatments (21 & 28 d) and a significant change in the levels of antioxidant enzymes was also produced mainly after 21 d. The deleterious effects of fentanyl and its analogues were further substantiated by corresponding histopathological changes in brain, liver and kidney (21 & 28 d). These compounds were also found to produce neuroadaptive changes as evidenced by the increased expression levels of c-Fos, glucocorticoid receptor, N-methyl-d-aspartate receptor1 and µ-opioid receptor (21 & 28 d). SIGNIFICANCE: Three novel analogues of fentanyl were envisaged to have alternative therapeutic potentials. However, their comparative sub-acute toxicity revealed undesirable side effects, thereby masking their therapeutic ability.


Assuntos
Fentanila/toxicidade , Animais , Biomarcadores/análise , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dano ao DNA/efeitos dos fármacos , Fentanila/análogos & derivados , Glutationa/análise , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/análise , Camundongos , Estresse Oxidativo/efeitos dos fármacos
3.
Toxicol Lett ; 325: 34-42, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070766

RESUMO

Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. Three experiments were conducted to evaluate the toxicity of carfentanil and the efficacy of naloxone in adult male African green monkeys. The first experiment determined the ED50 (found to be 0.71 µg/kg) of subcutaneous carfentanil for inducing bradypnea and/or loss of posture. Experiment 2 attempted to establish the ED50 of naloxone for rapidly reversing the bradypnea/loss of posture induced by carfentanil (1.15 µg/kg). Experiment 3 evaluated the effects of carfentanil (0.575 µg/kg) alone, the safety of naloxone (71-2841 µg/kg), and the efficacy of naloxone (71-710 µg/kg) administration at two time points following carfentanil (1.15 µg/kg) on operant choice reaction time. Collectively, these experiments characterized the temporal progression of carfentanil-induced toxic signs, determined the range of naloxone doses that restored respiratory and gross behavioral function, and determined the time course and range of naloxone doses that partially or completely reversed the effects of carfentanil on operant choice reaction time performance in African green monkeys. These results have practical relevance for the selection of opioid antagonists, initial doses, and expected functional outcomes following treatment of synthetic opioid overdose in a variety of operational/emergency response contexts.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Analgésicos Opioides/antagonistas & inibidores , Animais , Apneia/induzido quimicamente , Apneia/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Chlorocebus aethiops , Condicionamento Operante/efeitos dos fármacos , Overdose de Drogas/tratamento farmacológico , Fentanila/antagonistas & inibidores , Fentanila/toxicidade , Masculino , Naloxona/toxicidade , Antagonistas de Entorpecentes/toxicidade , Tempo de Reação/efeitos dos fármacos
4.
J Zoo Wildl Med ; 50(4): 993-996, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926534

RESUMO

Seven anesthesia events were performed over 6 wk on a 1.5-yr-old female okapi (Okapia johnstoni) being managed for a fetlock injury. A combination of butorphanol (B) (median; range) (0.045; 0.031-0.046 mg/kg), medetomidine (M) (0.037; 0.031-0.037 mg/kg), ketamine (K) (0.553; 0.536-1.071 mg/kg), and thiafentanil (T) (0.0045; 0.0040-0.0046 mg/kg) was administered in a padded stall. One dart containing all drugs was used for the first two anesthesias. Subsequently, BM was administered 10 min prior to KT using two darts. Time (median; range) from initial injection to first effects (6; 3-7 min) and recumbency (14; 4-20 min) were recorded. Induction quality with the one-dart protocol was poor or fair and was good or excellent with the two-dart protocol. Following recumbency, the okapi was intubated and ventilated, and physiological parameters were recorded. Anesthesia was consistently achieved with BMKT, but induction was smoother with the staged two-dart approach. Neither resedation nor renarcotization was observed post-reversal.


Assuntos
Antílopes/fisiologia , Butorfanol/farmacologia , Fentanila/análogos & derivados , Ketamina/farmacologia , Medetomidina/farmacologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Anestesia/veterinária , Animais , Butorfanol/administração & dosagem , Esquema de Medicação , Espécies em Perigo de Extinção , Feminino , Fentanila/administração & dosagem , Fentanila/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Ketamina/administração & dosagem , Medetomidina/administração & dosagem
5.
Forensic Sci Int ; 307: 110137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31927248

RESUMO

Seizures of synthetic opioids have increased since 2012, with a 45 % increase in synthetic opioid related deaths between 2016 and 2017 in US. Recently, concerns have arisen around these substances and their illicit use also in several European countries. Our aim was to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the analysis of 16 synthetic opioids in segmented hair, including fentanyl, norfentanyl, acetylfentanyl, U-47700, AH-7921, acrylfentanyl, crotonylfentanyl, butyrylfentanyl, methoxacetylfentanyl, U-49900, valeryfentanyl, 4-fluoro-iso-butyrylfentanyl, ocfentanyl, furanylfentanyl, tetrahydrofuranylfentanyl, and alfetanyl. Sample preparation involved washing the hair in dichloromethane, water and methanol, and extraction in methanol, followed by solid phase extraction clean-up. This method was validated for linearity, limit of quantification (LLOQ), precision and bias, selectivity, stability, matrix effects, extraction efficiency of the clean up procedure, and carryover. LLOQs ranged from 0.15-1pg/mg, and the calibration ranged from the LLOQ up to 500pg/mg. Intra and inter-day precision were evaluated at low and high concentrations, with spiked QCs, during 8 days and the results were satisfactory with RSD<15 % for all the compounds except for norfentanyl (22 %) and alfentanyl (19 %). Two external certified QCs containing fentanyl at 11 and 105pg/mg were also analysed within each batch and the RSD and bias were lower than 16 % and 10 %, respectively. Matrix effects compensated by internal standard fentanyl-d5 (MEIS), were between 77-115 % (RSD<10 %) and extraction efficiency of the clean-up procedure was between 66-93 % (RSD<21 %). Processed sample stability and carryover were acceptable for all of the compounds. The method was applied to 17 authentic hair samples (body or head hair) from US fentanyl analogue users. When head hair was available, the hair strands were analysed in 1cm/segment. Concentrations ranges were as follows: fentanyl (n=16) 2->ULOQ (500) pg/mg, norfentanyl (n=14) 1-38pg/mg, acetylfentanyl (n=7) 0.6->ULOQ (250) pg/mg, furanylfentanyl (n=5) 2-123pg/mg, tetrahydrofuranylfentanyl (n=1) 0.5-63pg/mg and valerylfentanyl (n=1) 2.1->ULOQ (50) pg/mg, along the hair strands. To our knowledge, this is the first time where concentrations of tetrahydrofuranylfentanyl, and valerylfentanyl in hair are reported. The same samples were also analysed for the determination of other drugs of abuse using our routine method (also in 1cm/segment for head hair when available). The results demonstrated poly-drug use in these fentanyl-analogue users population (mean drugs: n=5): amphetamine and/or methamphetamine (n=10), buprenorphine (n=5), cocaine (n=8), methadone (n=8), 6-MAM (n=17), meperidine (n=1), oxycodone (n=11), tramadol (n=3). Evaluation of the concentrations of these drugs, together with the fentanyl analogues is discussed in the present paper. Two authentic samples from two Belgian post-mortem cases, were also analysed showing fentanyl use and in one case polydrug use. The results demonstrated multi-analyte quantitative methods, including fentanyl analogues, are becoming useful in forensic laboratories involved in hair analysis, and in particular when polydrug use is suspected.


Assuntos
Analgésicos Opioides/análise , Fentanila/análogos & derivados , Fentanila/análise , Cabelo/química , Detecção do Abuso de Substâncias/métodos , Cromatografia Líquida de Alta Pressão/métodos , Toxicologia Forense/métodos , Humanos , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Medicamentos Sintéticos/análise , Espectrometria de Massas em Tandem/métodos
6.
Toxicol Lett ; 320: 109-112, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778775

RESUMO

BACKGROUND: Since 2016 an increase has been observed in the availability of new synthetic opioids (NSO) in Europe. Cyclopropylfentanyl is a very potent and selective µ-opioid agonist, which was reported for the first time in August 2017 in Europe. METHODS: The case was included in a prospective observational study of patients treated in emergency departments after the intake of novel psychoactive substances (NPS). Clinical features were acquired using a structured questionnaire for physicians. Serum and/or urine samples of ED patients were analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) screening methods for NPS. CASE REPORT: Within 10 min after intranasal intake of fentanyl, a 25-year-old male developed nausea, profuse sweating and dyspnoe. Because soon afterwards coma and respiratory insufficiency was noticed, the patient was admitted to hospital. After administration of naloxone (0.8 mg) breathing stabilized. However, the patient displayed recurrent decreases of oxygen saturation for 12 h. The intake of cyclopropylfentanyl was analytically confirmed. CONCLUSION: The constantly growing diversity of NSO still poses a high risk for drug users and can be a challenging task for clinicians and forensic toxicologists. Clinicians treating opioid overdoses should be aware of the potentially long lasting respiratory depression induced by fentanyl analogs.


Assuntos
Analgésicos Opioides/envenenamento , Overdose de Drogas/diagnóstico , Fentanila/análogos & derivados , Transtornos Relacionados ao Uso de Opioides , Detecção do Abuso de Substâncias/métodos , Administração Intranasal , Adulto , Aerossóis , Analgésicos Opioides/administração & dosagem , Cromatografia Líquida de Alta Pressão , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/fisiopatologia , Fentanila/administração & dosagem , Fentanila/envenenamento , Humanos , Masculino , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Resultado do Tratamento
7.
Toxicol Lett ; 320: 87-94, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812604

RESUMO

Human exposures to fentanyl analogs, which significantly contribute to the ongoing U.S. opioid overdose epidemic, can be confirmed through the analysis of clinical samples. Our laboratory has developed and evaluated a qualitative approach coupling liquid chromatography and quadrupole time-of-flight mass spectrometry (LC-QTOF) to address novel fentanyl analogs and related compounds using untargeted, data-dependent acquisition. Compound identification was accomplished by searching against a locally-established mass spectral library of 174 fentanyl analogs and metabolites. Currently, our library can identify 150 fentanyl-related compounds from the Fentanyl Analog Screening (FAS) Kit), plus an additional 25 fentanyl-related compounds from individual purchases. Plasma and urine samples fortified with fentanyl-related compounds were assessed to confirm the capabilities and intended use of this LC-QTOF method. For fentanyl, 8 fentanyl-related compounds and naloxone, lower reportable limits (LRL100), defined as the lowest concentration with 100 % true positive rate (n = 12) within clinical samples, were evaluated and range from 0.5 ng/mL to 5.0 ng/mL for urine and 0.25 ng/mL to 2.5 ng/mL in plasma. The application of this high resolution mass spectrometry (HRMS) method enables the real-time detection of known and emerging synthetic opioids present in clinical samples.


Assuntos
Analgésicos Opioides/sangue , Analgésicos Opioides/urina , Cromatografia Líquida de Alta Pressão , Fentanila/sangue , Fentanila/urina , Espectrometria de Massas por Ionização por Electrospray , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem , Analgésicos Opioides/síntese química , Cromatografia Líquida de Alta Pressão/normas , Fentanila/análogos & derivados , Fentanila/síntese química , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/normas , Detecção do Abuso de Substâncias/normas , Espectrometria de Massas em Tandem/normas
8.
Toxicol Lett ; 321: 90-94, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31881244

RESUMO

Potent opioids are increasingly responsible for morbidity and mortality in the Western world. Fentanyl and fentanyl derivatives are increasingly prevalent as adulterants or substitutes for opioid drugs of abuse in Europe and in North America. Trafficking and distribution of these chemicals evolve continuously and are poorly characterized at this time. Rescue and emergency personnel are increasingly concerned with the possibility of unintentional environmental exposures that might occur in the course of their operational duties. There is evidence that opioid agonists have been broadcast or applied directly in an offensive manner as incapacitating agents. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment.


Assuntos
Analgésicos Opioides/efeitos adversos , Substâncias para a Guerra Química/efeitos adversos , Tráfico de Drogas , Socorristas , Fentanila/efeitos adversos , Exposição Ocupacional/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Trabalho de Resgate , Descontaminação , Fentanila/análogos & derivados , Humanos , Exposição Ocupacional/prevenção & controle , Medição de Risco , Fatores de Risco
9.
Analyst ; 144(21): 6391-6403, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31579898

RESUMO

The opioid crisis and emergence of fentanyl, fentanyl analogues, and other synthetic opioids has highlighted the need for sensitive and robust detection for interdiction at screening points, notably vehicles at border crossings and packages at postal facilities. This work investigates the discriminative potential, sensitivity and specificity, of ion mobility spectrometry (IMS) for the detection of fentanyl and fifteen (15) fentanyl-related compounds (analogues, other opioids, and metabolites) relative to confounding environmental interferents. The environmental background interferent levels, frequency and intensity, were derived from over 10 000 screening samples collected from delivery vehicles entering a federal site. A receiver operating characteristic (ROC) curve methodology was employed to quantify the relationship between sensitivity and specificity for these target compounds on two instruments/configurations. These instrument configurations differed in desorption and drift tube temperatures, reactant ion dopant chemistry, and analysis time. This work identified reduced mobility areas of high interference that resulted in increased false positive rates (FPR), effectively reducing sensitivity (true positive rate: TPR) in those regions. Except for a few target compounds on either of the instruments that exhibited elevated FPRs, detection of fentanyl and fentanyl-related species was achieved at single to tens of nanograms with ≥90% TPR and ≤2% FPR. This work established the importance of systematic environmental background characterization at each specific screening setting in evaluating a platform's true performance.


Assuntos
Fentanila/análogos & derivados , Fentanila/análise , Espectrometria de Mobilidade Iônica/métodos , Meio Ambiente , Limite de Detecção , Curva ROC
10.
Nat Commun ; 10(1): 4493, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582737

RESUMO

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen's d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.


Assuntos
Encéfalo/patologia , Receptores Opioides mu/metabolismo , Esquizofrenia/patologia , Adulto , Analgésicos Opioides/administração & dosagem , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Feminino , Fentanila/administração & dosagem , Fentanila/análogos & derivados , Voluntários Saudáveis , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Traçadores Radioativos , Esquizofrenia/diagnóstico por imagem
11.
Toxicol Lett ; 317: 53-58, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31560942

RESUMO

In 2017, the U.S. Department of Health and Human Services and the White House declared a public health emergency to address the opioid crisis (Hargan, 2017). On average, 192 Americans died from drug overdoses each day in 2017; 130 (67%) of those died specifically because of opioids (Scholl et al., 2019). Since 2013, there have been significant increases in overdose deaths involving synthetic opioids - particularly those involving illicitly-manufactured fentanyl. The U.S. Drug Enforcement Administration (DEA) estimates that 75% of all opioid identifications are illicit fentanyls (DEA, 2018b). Laboratories are routinely asked to confirm which fentanyl or other opioids are involved in an overdose or encountered by first responders. It is critical to identify and classify the types of drugs involved in an overdose, how often they are involved, and how that involvement may change over time. Health care providers, public health professionals, and law enforcement officers need to know which opioids are in use to treat, monitor, and investigate fatal and non-fatal overdoses. By knowing which drugs are present, appropriate prevention and response activities can be implemented. Laboratory testing is available for clinically used and widely recognized opioids. However, there has been a rapid expansion in new illicit opioids, particularly fentanyl analogs that may not be addressed by current laboratory capabilities. In order to test for these new opioids, laboratories require reference standards for the large number of possible fentanyls. To address this need, the Centers for Disease Control and Prevention (CDC) developed the Traceable Opioid Material§ Kits product line, which provides over 150 opioid reference standards, including over 100 fentanyl analogs. These kits were designed to dramatically increase laboratory capability to confirm which opioids are on the streets and causing deaths. The kits are free to U.S based laboratories in the public, private, clinical, law enforcement, research, and public health domains.


Assuntos
Analgésicos Opioides/análise , Overdose de Drogas/diagnóstico , Fentanila/análise , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Kit de Reagentes para Diagnóstico/normas , Detecção do Abuso de Substâncias/normas , Analgésicos Opioides/classificação , Calibragem , Overdose de Drogas/mortalidade , Fentanila/análogos & derivados , Fentanila/classificação , Humanos , Transtornos Relacionados ao Uso de Opioides/mortalidade , Valor Preditivo dos Testes , Padrões de Referência , Reprodutibilidade dos Testes , Estados Unidos/epidemiologia
12.
Toxicol Lett ; 316: 127-135, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539569

RESUMO

Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Pulmão/efeitos dos fármacos , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Respiração/efeitos dos fármacos , Insuficiência Respiratória/prevenção & controle , Administração por Inalação , Aerossóis , Analgésicos Opioides/farmacocinética , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Fentanila/administração & dosagem , Fentanila/farmacocinética , Fentanila/toxicidade , Humanos , Pulmão/fisiopatologia , Masculino , Camundongos , Modelos Biológicos , Pletismografia Total , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia , Medição de Risco
13.
Forensic Sci Int ; 304: 109915, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31416646

RESUMO

Fatal intoxications due to accidental or voluntary intake of synthetic opioids represent an actual emerging issue. We report a case where we have analyzed furanyl fentanyl and its metabolite 4-anilino-N-phenetyl-piperidine (4-ANPP) in blood, urine, gastric content, bile and cerebrospinal fluid. In this case, a 53-year-old man was found dead at home with a needle still inserted in a vein; a plastic bag containing a white powder (later identified as a furanyl fentanyl-based product) was discovered in the room. Biological samples were collected during autopsy and extracted/purified onto a SPE cartridge before instrumental analysis. Qualitative and quantitative analyses were performed by LC-MS/MS on peripheral and cardiac blood, urine, cerebrospinal fluid (CSF), bile and gastric content. Furanyl fentanyl was identified and quantified in all the biological fluids collected. Interestingly, gastric content revealed an unexpected high amount of furanyl fentanyl; yet, cardiac blood and femoral blood provided significantly different concentrations (11.8 and 2.7 ng/g respectively). The concentration of furanyl fentanyl in CSF was similar to that measured in femoral blood (2.6 ng/mL), thus confirming that CSF could be a good alternative biological fluid whenever a postmortem redistribution is suspected. Concentrations of 93.5, 50.4, 171.7, 41.9, 10.2 ng/mL(g) were measured for 4-ANPP in cardiac blood, femoral blood, urine, bile and cerebrospinal fluid, respectively. The outcomes from the presented case report suggest that the two substances have been not only injected intravenously, but probably also ingested by the man. Fentanyl derivative and its precursor seemed to undergo an extensive postmortem redistribution.


Assuntos
Analgésicos Opioides/análise , Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Furanos/análise , Furanos/farmacocinética , Mudanças Depois da Morte , Bile/química , Cromatografia Líquida , Fentanila/análise , Fentanila/farmacocinética , Toxicologia Forense/métodos , Conteúdo Gastrointestinal/química , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/complicações , Medicamentos Sintéticos/análise , Medicamentos Sintéticos/farmacocinética
14.
Forensic Sci Int ; 302: 109896, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426021

RESUMO

BACKGROUND: Interpretation of postmortem fentanyl concentrations after transdermal application remains a challenge. There are indications that fentanyl shows relevant postmortem redistribution. The aim of this study was to investigate the time course of these changes and to develop recommendations for toxicological case work. MATERIAL AND METHOD: Blood specimens were collected from palliative care patients who were treated with fentanyl transdermal patches. Antemortem reference samples (ethylenediaminetetraacetic acid (EDTA) and serum specimens) were collected at stable dose rates. Postmortem femoral venous blood specimens were collected at four postmortem time-points: 2hpm (hours postmortem), 6-8hpm, 11-16hpm and approximately 24hpm. Liquid chromatography tandem mass spectrometry was applied to quantify fentanyl and norfentanyl. RESULTS: Ten patients were included in the study (8 men, 2 women). Fentanyl patches with delivery rates of 12-150µg/h were applied. Antemortem fentanyl levels in EDTA samples varied between 0.19 and 4.64µg/L. At 6 to 8hpm, blood concentrations of fentanyl were already significantly (p=0.05) higher in postmortem samples compared to the paired antemortem reference. On average, the antemortem concentration (range: 0.19-4.64µg/L) increased 3-fold within 6-8hpm (range: 0.4-14.9µg/L), and 5.5-fold within 24hpm (range: 0.39-21.88µg/L). Norfentanyl concentrations increased significantly (p=0.01) within 6-8hpm, too. In half of the patients, norfentanyl concentrations were below fentanyl concentrations, antemortem as well as postmortem. CONCLUSION: Postmortem fentanyl concentrations increased quickly. As early as 6-8h after death, postmortem concentrations differ significantly from antemortem ones. Our results strongly indicate that postmortem blood concentrations of fentanyl after transdermal application should be interpreted carefully.


Assuntos
Analgésicos Opioides/sangue , Fentanila/sangue , Mudanças Depois da Morte , Adesivo Transdérmico , Idoso , Analgésicos Opioides/administração & dosagem , Cromatografia Líquida , Ácido Edético , Feminino , Fentanila/administração & dosagem , Fentanila/análogos & derivados , Toxicologia Forense , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
15.
J Mass Spectrom ; 54(9): 729-737, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31432563

RESUMO

Fentanyl and related psychoactive substances are at the forefront of the opioid overdose crisis, for which a complete solution is not immediately obvious. Drug testing for harm reduction may be an effective approach to both reduce overdoses and importantly, engage people who use drugs (PWUD) with the medical system. Paper spray mass spectrometry (PS-MS) is an ambient ionization strategy that is uniquely suited to address this complicated analytical task. This perspectives article presents the merits of PS-MS, with a focus upon the current state of its use as a candidate drug checking strategy for harm reduction. PS-MS is inherently sensitive and selective, with detection limits in the picogram range. It requires small drug samples (~1 mg) for quantitative drug testing, critical to encourage pre-consumption measurements by PWUD in the context of a harm reduction strategy. Calibrations obtained in surrogate drug matrices containing highly concentrated primary drugs demonstrate comparable sensitivities, a wide calibration range, and minimal matrix effects. PS-MS can be interfaced with high-resolution MS for non-targeted analysis, allowing the identification of novel psychoactive substances as they appear in street drugs. Individual quantitative PS-MS measurements for drug testing can be done in 1 minute or less, resulting in high sample throughput. Significant advancement in mass spectrometer miniaturization and mobilization has concomitant benefits for direct, on-site drug checking, such as reduced cost, simplified maintenance and ease of use by less skilled operators. While PS-MS technology continues to rapidly advance, it is our opinion that PS-MS can be utilized as an effective tool for harm reduction in the opioid overdose crisis.


Assuntos
Overdose de Drogas/prevenção & controle , Fentanila/análogos & derivados , Fentanila/análise , Espectrometria de Massas/instrumentação , Espectrometria de Massas/métodos , Psicotrópicos/análise , Redução do Dano , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Humanos , Limite de Detecção , Miniaturização , Sensibilidade e Especificidade , Detecção do Abuso de Substâncias/métodos , Fatores de Tempo
16.
Sci Justice ; 59(4): 459-466, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31256819

RESUMO

Since the introduction of the European Early Warning System in 2005, >700 new psychoactive substances (NPS) have been listed. This review article presents for the first time the Swiss narcotic law in perspective of scheduling of NPS, and compares it to the regulations of the German speaking neighbours Austria and Germany. The Swiss way is a fast and effective way for scheduling NPS, with the purpose to restrict drug trafficking and for controlling the NPS drug market: the legal basis for scheduling substances of abuse is the "Law about narcotics and psychotropic substances" (BetmG, SR 812.121), which includes the "narcotic law directory (BetmVV-EDI, SR 812.121.11) suitable for listing all controlled substances. The BetmVV-EDI, SR 812.121.11 contains seven indices, with index e specifically designed for the fast scheduling of NPS. Newly appearing NPS can either be controlled under a structure analogues definition or by listing single substances. The list of single substances is updated at least once per year, and structure analogues definitions can be implemented, in order to keep track with new developments on the NPS market. The latest version from November 30th 2018 contains ten different structure analogue definitions and 207 single substances. Requirements to list NPS are their appearance on the NPS market, suspected psychotropic effects and their suggestions by Forensic professionals. As soon as substances are newly placed, on Schedule I of the 1961 Convention or Schedule II of the 1971 Convention by the Commission on Narcotic Drugs of the World Health Organization they can easily be transferred from index e to index a-d of the BetmVV-EDI, SR 812.121.11. The Austrian law uses a structure analogue and single substances approach (introduced in 2012, one update in 2016), whereas the German NPS law (established in 2016, no update yet) only lists two structure-analogue-definitions. All three legislations have defined which core structures, kinds and sites of substitutions are regulated.


Assuntos
Substâncias Controladas/classificação , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Entorpecentes/classificação , Psicotrópicos/classificação , Medicamentos Sintéticos/classificação , Alcaloides , Áustria , Canabinoides , Fentanila/análogos & derivados , Alemanha , Fenetilaminas , Suíça , Nações Unidas
17.
Forensic Sci Int ; 302: 109858, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279508

RESUMO

Fentanyl is a potent synthetic opioid with a variety of possible applications. Transdermal fentanyl patches are regularly prescribed for patients with severe chronic or cancer-related pain. The potential for abuse is well-known and cases associated with illicit fentanyl intake are common. Fentanyl related fatalities due to unintentional misuse are relatively rare. This study focused on those instances and their identification in forensic examinations and adds new cases and consolidates the existing femoral blood concentrations in the event of fatal fentanyl patch misapplications. A total of 35 cases between 2010 and 2018 in which transdermal fentanyl patches were detected during forensic autopsies were identified and reviewed for the frequency of unspecific macroscopic signs of opioid intoxication. Furthermore, a detailed examination is presented for 11 cases in which toxicological results were available. The cause of death was eventually considered to be related to fentanyl patch misuse in 5 of these 11 cases. Co-administered drugs and signs of opioid intoxication, especially pulmonary edema, were frequently found. Lastly, it is advised to include norfentanyl and hair analysis in the interpretation of post-mortem fentanyl concentrations.


Assuntos
Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Uso Indevido de Medicamentos sob Prescrição , Adesivo Transdérmico/efeitos adversos , Adolescente , Adulto , Idoso , Analgésicos Opioides/análise , Analgésicos Opioides/envenenamento , Cromatografia Líquida , Feminino , Fentanila/análogos & derivados , Fentanila/análise , Fentanila/envenenamento , Cabelo/química , Humanos , Masculino , Espectrometria de Massas , Edema Pulmonar/patologia , Estudos Retrospectivos , Retenção Urinária/patologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-31177051

RESUMO

The abuse of fentanyl and its analogues, which are potent, short-acting, synthetic narcotic analgesics, has become a major issue. Many cases containing fentanyl-analogue and novel synthetic opioids have also been reported. Hence, we report the determination of fentanyl, fentanyl-analogue and novel synthetic opioids in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method is characterized by the use of a simple, fast and inexpensive liquid-liquid extraction (LLE) for sample preparation, a rapid run time (8 min) and a low required volume of whole blood (100 µl). The limits of detection (LODs) ranged from 0.005 to 0.03 ng/ml, and the lower limits of quantitation (LLOQs) ranged from 0.05 to 0.2 ng/ml. The method was shown to be liner over a concentration range of 0.2-40 ng/ml for fentanyl, norfentanyl and norcarfentanil and 0.05-40 ng/ml for all other target analytes. Recoveries were within the range of 72.09%-103.22%, and the matrix effects were in the 67.95%-113.32% range. Moreover, the method was applied to the detection and quantification of fentanyl and its analogues in whole blood from real forensic cases. This methodology has great potential for use in the determination of fentanyl and its analogues in forensic cases.


Assuntos
Analgésicos Opioides/sangue , Cromatografia Líquida de Alta Pressão/métodos , Fentanila/sangue , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem/métodos , Analgésicos Opioides/síntese química , Feminino , Fentanila/análogos & derivados , Medicina Legal , Humanos , /química , Masculino , Pessoa de Meia-Idade
19.
J Forensic Sci ; 64(6): 1735-1742, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31216059

RESUMO

The National Institute on Drug Abuse has observed an increase in fentanyl deaths in the United States. One epidemic related to the abuse of fentanyl happened in Cook County in 2005-2007 (350 deaths). Another outbreak of fentanyl deaths occurred in 2015-2017 in the same area. The database of the Cook County Medical Examiner's Office was searched for cases of fentanyl deaths between 2015 and 2017: 1244 deaths were found. A comparison was performed with the previous data: an increase in the number of females was observed in 2015-2017. Also, in 2005-2007, the majority of deaths occurred among African American, while in 2015-2017, Caucasians were more involved. Within our population, some drug combinations were more common in specific demographic subgroups (male/females; Caucasian/African American; and certain age groups). The epidemiology and the most significant drug associations found at the toxicology are discussed, highlighting the usefulness of the knowledge about this outbreak for public health.


Assuntos
Analgésicos Opioides/envenenamento , Overdose de Drogas/mortalidade , Fentanila/envenenamento , Transtornos Relacionados ao Uso de Opioides/mortalidade , Adolescente , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Analgésicos Opioides/análise , Depressores do Sistema Nervoso Central/análise , Médicos Legistas , Etanol/análise , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Fentanila/análogos & derivados , Fentanila/análise , Humanos , Illinois/epidemiologia , Rim/química , Fígado/química , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Estudos Retrospectivos , Distribuição por Sexo , Adulto Jovem
20.
Fa Yi Xue Za Zhi ; 35(2): 216-223, 2019 Apr.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-31135118

RESUMO

Abstract: Objective To provide the reference for the identification of unknown fentanyl analogues by studying the characteristic ions and main fragmentation pathways of fentanyl analogues in the modes of collision induced dissociation (CID) and electron ionization (EI). Methods Nine fentanyl analogues (2, 2'-difluorofentanyl, acetyl fentanyl, fentanyl, butyl fentanyl, valeryl fentanyl, acryloyl fentanyl, furan fentanyl, 4-fluorine isobutyl fentanyl, carfentanyl) were selected and analyzed with ultra-high performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS) and gas chromatography-mass spectrometry (GC-MS). The mass spectrum obtained was analyzed. The CID and EI fragmentation routes of fentanyl analogues were speculated. Results The CID and EI fragmentation pathways were highly similar. In the CID mode, characteristic ions were formed by the carbon-nitrogen bond cleavage between the piperidine ring and the N-phenyl-amide moiety, within the piperidine ring, and between the phenethyl and piperidine ring. While in the EI mode, dissociation of the piperidine ring, as well as cleavage between the piperidine ring and the phenethyl were the main fragmentation pathways. Conclusion This study summarizes the main fragmentation pathways and characteristic ions of fentanyl analogues in the CID and EI modes, which is useful for forensic laboratories to identify and structural analyze fentanyl type new psychoactive substance in practical work.


Assuntos
Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Fentanila/análise , Cromatografia Gasosa-Espectrometria de Massas , Espectrometria de Massas , Fentanila/análogos & derivados , Humanos
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