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1.
Toxicol Appl Pharmacol ; 419: 115483, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722667

RESUMO

The number of new psychoactive substances (NPS) on the illicit drug market increases fast, posing a need to urgently understand their toxicity and behavioural effects. However, with currently available rodent models, NPS assessment is limited to a few substances per year. Therefore, zebrafish (Danio rerio) embryos and larvae have been suggested as an alternative model that would require less time and resources to perform an initial assessment and could help to prioritize substances for subsequent evaluation in rodents. To validate this model, more information on the concordance of zebrafish larvae and mammalian responses to specific classes of NPS is needed. Here, we studied toxicity and behavioural effects of opioids in zebrafish early life stages. Synthetic opioids are a class of NPS that are often used in pain medication but also frequently abused, having caused multiple intoxications and fatalities recently. Our data shows that fentanyl derivatives were the most toxic among the tested opioids, with toxicity in the zebrafish embryo toxicity test decreasing in the following order: butyrfentanyl>3-methylfentanyl>fentanyl>tramadol> O-desmethyltramadol>morphine. Similar to rodents, tramadol as well as fentanyl and its derivatives led to hypoactive behaviour in zebrafish larvae, with 3-methylfentanyl being the most potent. Physico-chemical properties-based predictions of chemicals' uptake into zebrafish embryos and larvae correlated well with the effects observed. Further, the biotransformation pattern of butyrfentanyl in zebrafish larvae was reminiscent of that in humans. Comparison of toxicity and behavioural responses to opioids in zebrafish and rodents supports zebrafish as a suitable alternative model for rapidly testing synthetic opioids.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Peixe-Zebra/embriologia , Analgésicos Opioides/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Biotransformação , Carga Corporal (Radioterapia) , Relação Dose-Resposta a Droga , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fentanila/análogos & derivados , Fentanila/farmacocinética , Larva/efeitos dos fármacos , Larva/metabolismo , Locomoção/efeitos dos fármacos , Modelos Animais , Reprodutibilidade dos Testes , Especificidade da Espécie , Toxicocinética , Peixe-Zebra/metabolismo
2.
PLoS One ; 15(6): e0234683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544184

RESUMO

Rapid resuscitation of an opioid overdose with naloxone, an opioid antagonist, is critical. We developed an opioid receptor quantitative systems pharmacology (QSP) model for evaluation of naloxone dosing. In this model we examined three opioid exposure levels that have been reported in the literature (25 ng/ml, 50 ng/ml, and 75 ng/ml of fentanyl). The model predicted naloxone-fentanyl interaction at the mu opioid receptor over a range of three naloxone doses. For a 2 mg intramuscular (IM) dose of naloxone at lower fentanyl exposure levels (25 ng/ml and 50 ng/ml), the time to decreasing mu receptor occupancy by fentanyl to 50% was 3 and 10 minutes, respectively. However, at a higher fentanyl exposure level (75 ng/ml), a dose of 2 mg IM of the naloxone failed to reduce mu receptor occupancy by fentanyl to 50%. In contrast, naloxone doses of 5 mg and 10 mg IM reduced mu receptor occupancy by fentanyl to 50% in 5.5 and 4 minutes respectively. These results suggest that the current doses of naloxone (2 mg IM or 4 mg intranasal (IN)) may be inadequate for rapid reversal of toxicity due to fentanyl exposure and that increasing the dose of naloxone is likely to improve outcomes.


Assuntos
Ligação Competitiva , Fentanila/metabolismo , Modelos Teóricos , Naloxona/administração & dosagem , Receptores Opioides mu/metabolismo , Analgésicos Opioides/metabolismo , Simulação por Computador , Relação Dose-Resposta a Droga , Overdose de Drogas/tratamento farmacológico , Fentanila/toxicidade , Humanos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/administração & dosagem , Resultado do Tratamento
3.
J Spec Oper Med ; 20(1): 55-59, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203607

RESUMO

PURPOSE: This study investigated the decontamination effectiveness of selected toxic industrial chemicals using RSDL® (Reactive Skin Decontamination Lotion Kit; Emergent BioSolutions Inc.; https://www.rsdl.com/). MATERIALS AND METHODS: Quantitative analytical methods were developed for dermal toxic compounds of varying physicochemical properties: sulfuric acid, hydrofluoric acid, ammonia, methylamine, hydrazine, phenylhydrazine, 1,2-dibromoethane, capsaicin, and fentanyl. These methods were subsequently used to evaluate the decontamination effectiveness on painted metal substrates at an initial chemical contamination level of 10g/m2 (0.1g/m2 for fentanyl). RESULTS: The decontamination effectiveness ranged from 97.79% to 99.99%. DISCUSSION AND CONCLUSION: This study indicates that the RSDL kit may be amenable for use as an effective decontaminant for material substrates beyond the classical chemical warfare agents and the analytical methods may be used for future decontamination assessment studies using contaminated skin or other materials.


Assuntos
Substâncias para a Guerra Química/toxicidade , Descontaminação/métodos , Fentanila/toxicidade , Administração Cutânea , Humanos , Pele
4.
Anesthesiology ; 132(5): 1138-1150, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044798

RESUMO

BACKGROUND: As severe acute hypoxemia produces a rapid inhibition of the respiratory neuronal activity through a nonopioid mechanism, we have investigated in adult rats the effects of hypoxemia after fentanyl overdose-induced apnea on (1) autoresuscitation and (2) the antidotal effects of naloxone. METHODS: In nonsedated rats, the breath-by-breath ventilatory and pulmonary gas exchange response to fentanyl overdose (300 µg · kg · min iv in 1 min) was determined in an open flow plethysmograph. The effects of inhaling air (nine rats) or a hypoxic mixture (fractional inspired oxygen tension between 7.3 and 11.3%, eight rats) on the ability to recover a spontaneous breathing rhythm and on the effects of naloxone (2 mg · kg) were investigated. In addition, arterial blood gases, arterial blood pressure, ventilation, and pulmonary gas exchange were determined in spontaneously breathing tracheostomized urethane-anesthetized rats in response to (1) fentanyl-induced hypoventilation (7 rats), (2) fentanyl-induced apnea (10 rats) in air and hyperoxia, and (3) isolated anoxic exposure (4 rats). Data are expressed as median and range. RESULTS: In air-breathing nonsedated rats, fentanyl produced an apnea within 14 s (12 to 29 s). A spontaneous rhythmic activity always resumed after 85.4 s (33 to 141 s) consisting of a persistent low tidal volume and slow frequency rhythmic activity that rescued all animals. Naloxone, 10 min later, immediately restored the baseline level of ventilation. At fractional inspired oxygen tension less than 10%, fentanyl-induced apnea was irreversible despite a transient gasping pattern; the administration of naloxone had no effects. In sedated rats, when PaO2 reached 16 mmHg during fentanyl-induced apnea, no spontaneous recovery of breathing occurred and naloxone had no rescuing effect, despite circulation being maintained. CONCLUSIONS: Hypoxia-induced ventilatory depression during fentanyl induced apnea (1) opposes the spontaneous emergence of a respiratory rhythm, which would have rescued the animals otherwise, and (2) prevents the effects of high dose naloxone.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Hipóxia/fisiopatologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Vigília/efeitos dos fármacos , Animais , Hipnóticos e Sedativos/toxicidade , Hipóxia/induzido quimicamente , Hipóxia/tratamento farmacológico , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Índice de Gravidade de Doença , Vigília/fisiologia
5.
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
6.
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
8.
Clin Toxicol (Phila) ; 58(6): 460-465, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31475588

RESUMO

Background: Overdose deaths from fentanyl and its analogs have increased significantly since 2013. There are limited data regarding the prevalence of fentanyl exposure among emergency department (ED) patients with active opioid use.Methods: We conducted a cross-sectional study at an urban hospital from May 20 to July 30, 2018. A convenience sample of adult ED patients with active opioid use, defined as opioid use within seven days prior to ED visit, were enrolled. Rapid Response® Single Drug Test Strip (BTNX Inc., Markham, Canada) was used to detect fentanyl in urine samples. Information on demographic, substance use history, and knowledge of fentanyl was obtained using a brief survey tool. Our primary outcome was the prevalence of fentanyl exposure; secondary outcomes included patients' knowledge regarding potency, risk of overdose death from fentanyl and intentional purchase of fentanyl.Results: During our study period, 451 patients reported active substance use. Of these, 208 reported active opioid use and 165 consented for the study. The median age was 49 years [interquartile range: 38, 57] and 77.0% (n = 127) were male; 42 participants (25.5%) presented to ED after an acute overdose event. Heroin was the preferred opioid of use in 90.8% of the participants, primarily via intranasal route (64.6%). Polysubstance use was reported in 98.8%, most commonly with cocaine (57.6%; n = 95). Fentanyl was detected in 104 out of 129 urine samples tested (80.6%). 84.2% (n = 139) identified fentanyl as highly potent and 85.5% (n = 141) recognized highest risk of death in fentanyl overdose. A larger proportion of non-overdose participants intentionally purchased fentanyl (34.1%; n = 42) compared to the overdose group (16.7%, n = 7; p = .04).Conclusions: The majority of ED patient with active opiate use were exposed to fentanyl while one in three participants intentionally purchased fentanyl despite their awareness of its potency and the high-risk of death from overdose.


Assuntos
Analgésicos Opioides/toxicidade , Serviço Hospitalar de Emergência/estatística & dados numéricos , Fentanila/toxicidade , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Analgésicos Opioides/urina , Baltimore/epidemiologia , Estudos Transversais , Feminino , Fentanila/urina , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/urina , Prevalência , Risco , Detecção do Abuso de Substâncias , População Urbana/estatística & dados numéricos
9.
Clin Toxicol (Phila) ; 58(2): 112-116, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31092055

RESUMO

Introduction: Deaths due to drug overdose in the US in 2017 amounted to approximately 72,000, an increase of 12% from the previous year. There was a near tenfold increase in deaths involving synthetic opioids from 3,105 in 2013 to approximately 30,000 in 2017. Recent data from the United States (US) Centers for Disease Control and Prevention (CDC) identified fentanyl as most frequently involved in overdose deaths in the US as of 2016. This is consistent with statistics in New York State, where opioid-related overdose deaths increased by nearly 35% between 2015 and 2016, with fentanyl-related deaths increasing by 160%. The objective of this study is to report the incidence of deaths involving fentanyl and fentanyl analogs across five counties in Central New York between January 1, 2013 and December 17, 2017.Methods: All unintentional drug-related deaths across five counties in Central New York between January 1, 2013 and December 17, 2017 reported by the Medical Examiner's (ME) Office were included. Ante-mortem and post-mortem specimens were obtained for analysis.Results: A total of 417 deaths involving fentanyl and/or fentanyl analogs were reported, increasing from 10 cases in 2013 to 184 cases in 2017. Despropionyl fentanyl and furanylfentanyl were the analogs identified most frequently.Discussion: The study's data demonstrates an increase in the number of deaths related to fentanyl and/or fentanyl analogs. The number of deaths associated with fentanyl or an analog rose year to year, with despropionyl fentanyl and furanylfentanyl most commonly identified. The increase in fentanyl- and/or fentanyl analog-related deaths is consistent with national and international data.Conclusions: This study highlights the current crisis occurring in Central New York and serves to emphasize the ongoing global health threat posed by these chemical derivatives.


Assuntos
Analgésicos Opioides/toxicidade , Overdose de Drogas/mortalidade , Fentanila , Transtornos Relacionados ao Uso de Opioides/mortalidade , Fentanila/análogos & derivados , Fentanila/toxicidade , Humanos , Incidência , New York/epidemiologia
11.
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
12.
J Neurosci ; 39(36): 7061-7073, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31300521

RESUMO

Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 µg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 µg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a µ-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4+ and IB4- neurons. This sensitizing effect of fentanyl was reversed in weakly IB4+ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.SIGNIFICANCE STATEMENT Clinically used µ-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid-naive and opioid-primed animals, and provide evidence for the important role of nociceptor µ-opioid receptor-mediated calcium signaling and peripheral protein translation in the weakly IB4-binding population of nociceptors in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Hiperalgesia/fisiopatologia , Plasticidade Neuronal , Nociceptores/efeitos dos fármacos , Potenciais de Ação , Animais , Sinalização do Cálcio , Gânglios Espinais/citologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Nociceptores/metabolismo , Nociceptores/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo
13.
J Urban Health ; 96(3): 353-366, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168735

RESUMO

Safe consumption spaces (SCS) are evidence-based interventions that reduce drug-related morbidity and mortality operating in many countries. However, SCS are yet to be widely implemented in the USA despite the escalating overdose epidemic. The aim of this multi-city study was to identify the factors associated with willingness to use a SCS among people who use drugs (PWUD) in Baltimore, Providence, and Boston, stratified by injection drug use status. Our secondary aim was to characterize the anticipated barriers to accessing SCS if they were to be implemented in these cities. PWUD were invited to complete a cross-sectional survey in 2017. The analysis was restricted to 326 opioid users (i.e., heroin, fentanyl, and non-medical opioid pill use). The majority (77%) of participants expressed willingness to use a SCS (Baltimore, 78%; Providence, 68%; Boston. 84%). Most respondents were male (59%), older than 35 years (76%), non-white (64%), relied on public/semi-public settings to inject (60%), had a history of overdose (64%), and recently suspected fentanyl contamination of their drugs (73%). A quarter (26%) preferred drugs containing fentanyl. Among injectors, female gender, racial minority status, suspicion of drugs containing fentanyl, and drug use in public/semi-public settings were associated with higher willingness to use a SCS; prior arrest was associated with lower willingness. Among non-injectors, racial minority status, preference for fentanyl, and drug use in public/semi-public settings were associated with higher willingness, whereas recent overdose held a negative association. The most commonly anticipated barriers to accessing a SCS in the future were concerns around arrest (38%), privacy (34%), confidentiality/trust/safety (25%), and cost/time/transportation (16%). These data provide evidence of high SCS acceptability among high-risk PWUD in the USA, including those who prefer street fentanyl. As SCS are implemented in the USA, targeted engagement efforts may be required to reach individuals exposed to the criminal justice system.


Assuntos
Atitude , Overdose de Drogas/epidemiologia , Overdose de Drogas/prevenção & controle , Fentanila/toxicidade , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Adulto , Fatores Etários , Cidades , Confidencialidade , Grupos de Populações Continentais , Estudos Transversais , Feminino , Humanos , Aplicação da Lei , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Abuso de Substâncias por Via Intravenosa/epidemiologia , Confiança , Estados Unidos/epidemiologia , População Urbana
14.
Neuropharmacology ; 158: 107596, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30965021

RESUMO

The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. The present study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 µg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1-2 h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 µg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.


Assuntos
Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Analgésicos Opioides/metabolismo , Analgésicos Opioides/toxicidade , Animais , Catalepsia/induzido quimicamente , Cromatografia Líquida de Alta Pressão , Fentanila/metabolismo , Fentanila/farmacocinética , Fentanila/toxicidade , Meia-Vida , Hipotermia/induzido quimicamente , Injeções Subcutâneas , Masculino , Dinâmica não Linear , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
15.
Clin Toxicol (Phila) ; 57(9): 806-812, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30775936

RESUMO

Introduction: Fentanyl derivatives like cyclopropylfentanyl have recently appeared on the recreational drug market. Cyclopropylfentanyl is probably a highly potent opioid, but human toxicological data are not available so far. Similar to other fentanyl derivatives the most serious acute health risk due to the use of cyclopropylfentanyl is likely to be respiratory depression. In case of overdose, this may lead to apnoea, respiratory arrest and death. In this paper, we present three cases of severe intoxication with cyclopropylfentanyl. Methods: Observational case series including three intoxications treated in the Emergency Department at the University Medical Centre in 2017. In all cases, the consumption of any drugs was denied by the patients and relatives. Toxicological analyses using GC-MS, LC-QTOF-MS and LC-MS-MS of serum, urine samples and in one case of a powder sample, found in the hospital room, were performed. Medical records were reviewed to obtain clinical data. Results: Clinical effects of severe opioid intoxications comprising loss of consciousness, bradypnea, hypercapnia, arterial hypotension and miosis were recorded. In all cases, the novel fentanyl analogue cyclopropylfentanyl was detected in body fluids. In two cases further synthetic opioids (U-47700, methoxyacetylfentanyl, butyrfentanyl, 2-fluoroiso- or 4-fluoroisobutyrfentanyl) and mitragynine or desoxypipradrol were found. A discovered powder sample contained cyclopropylfentanyl, cyclopropylnorfentanyl, acetylfentanyl, 4-ANPP, U-47700 and caffeine. Except for acetylfentanyl all ingredients could be detected in the respective blood and urine sample. In two cases a cyclopropylfentanyl serum concentration of 51 and 76 ng/ml was determined. Discussion: In three cases of severe potentially life-threatening intoxication, cyclopropylfentanyl was verified using different analytical procedures. The ingested substance, as well as the excreted metabolites, were detected by application of various mass spectrometric techniques. Conclusions: In cases of intoxication without a medical history, the detailed toxicological analysis may reveal new psychoactive substances which are not detected by standard toxicological screening approaches. The high pharmacological potency of new products with unknown toxicological data and unknown synergistic effects may easily lead to a life-threatening overdose.


Assuntos
Analgésicos Opioides/toxicidade , Coma/induzido quimicamente , Overdose de Drogas/complicações , Fentanila/análogos & derivados , Insuficiência Respiratória/induzido quimicamente , Adulto , Analgésicos Opioides/sangue , Analgésicos Opioides/urina , Overdose de Drogas/sangue , Overdose de Drogas/diagnóstico , Overdose de Drogas/urina , Fentanila/sangue , Fentanila/toxicidade , Fentanila/urina , Humanos , Masculino
16.
Can J Anaesth ; 66(4): 414-421, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30666589

RESUMO

Carfentanil is a synthetic fentanyl analogue approved for veterinary use. It is a mu-opioid receptor agonist with an estimated analgesic potency approximately 10,000 times that of morphine and 20-30 times that of fentanyl, based on animal studies. Since 2016, an increasing number of reports describe detection of carfentanil in the illicit drug supply. Little is known about the pharmacology of carfentanil in humans. Its high potency and presumed high lipophilicity, large volume of distribution, and potential active metabolites have raised concerns about the management of people exposed to carfentanil as well as the safety of first responders. Exposed individuals exhibit features of an opioid toxidrome and respond to opioid antagonists such as naloxone, although empiric dose requirements are unknown and very high doses may be required. Rare reports of suspected accidental poisoning of first responders have not been analytically confirmed and are unlikely to represent true poisoning. General occupational hygiene measures, including regular decontamination with soap and water, basic personal protective equipment (nitrile gloves, N95 mask, and eye goggles), and ready access to naloxone are generally sufficient in most circumstances.


Assuntos
Analgésicos Opioides/administração & dosagem , Fentanila/análogos & derivados , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Analgésicos Opioides/farmacologia , Analgésicos Opioides/toxicidade , Animais , Fentanila/administração & dosagem , Fentanila/farmacologia , Fentanila/toxicidade , Humanos , Drogas Ilícitas/provisão & distribução , Drogas Ilícitas/toxicidade , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/complicações , Saúde Pública , Drogas Veterinárias/administração & dosagem , Drogas Veterinárias/farmacologia , Drogas Veterinárias/toxicidade
17.
Neuropsychopharmacol Rep ; 39(1): 17-35, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30506634

RESUMO

BACKGROUND: Fentanyl, a synthetic opioid categorized as a narcotic analgesic, has a 100- to 200-fold stronger effect than most opioids, such as morphine. Fatal accidents due to chronic use and abuse of fentanyl are a worldwide social problem. One reason for the abuse of fentanyl is its psychostimulant effects that could induce behavioral changes. The effects of chronic fentanyl administration on behavior, however, are unclear. METHODS: Adult male C57BL/6J mice were chronically administered fentanyl (0.03 or 0.3 mg/kg/d i.p.), and various behaviors were assessed using a behavioral test battery. RESULTS: Mice chronically administered a high dose of fentanyl (0.3 mg/kg/d) exhibited decreased anxiety-like behavior as assessed by the open field and elevated plus maze tests. On the other hand, interruption of fentanyl administration led to increased anxiety-like behavior as observed in the light and dark transition test. The hot plate test revealed that chronic administration of fentanyl reduced pain sensitivity. High-dose chronic fentanyl administration reduced the locomotor stimulatory effects of cocaine. The results, however, failed to reach the threshold for study-wide statistical significance. CONCLUSION: Chronic fentanyl administration induces some behavioral changes in mice. Although further studies are needed to clarify the underlying mechanisms of the behavioral effects of chronic fentanyl administration, our findings suggest that fentanyl is safe under properly controlled conditions.


Assuntos
Ansiedade/etiologia , Fentanila/toxicidade , Entorpecentes/toxicidade , Animais , Fentanila/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Entorpecentes/farmacologia
18.
J Pharmacol Exp Ther ; 368(2): 282-291, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30409833

RESUMO

Fentanyl is an extremely potent synthetic opioid that has been increasingly used to adulterate heroin, cocaine, and counterfeit prescription pills, leading to an increase in opioid-induced fatal overdoses in the United States, Canada, and Europe. A vaccine targeting fentanyl could offer protection against the toxic effects of fentanyl in both recreational drug users and others in professions at risk of accidental exposure. This study focuses on the development of a vaccine consisting of a fentanyl-based hapten (F) conjugated to keyhole limpet hemocyanin (KLH) carrier protein or to GMP-grade subunit KLH (sKLH). Immunization with F-KLH in mice and rats reduced fentanyl-induced hotplate antinociception, and in rats reduced fentanyl distribution to the brain compared with controls. F-KLH did not reduce the antinociceptive effects of equianalgesic doses of heroin or oxycodone in rats. To assess the vaccine effect on fentanyl toxicity, rats immunized with F-sKLH or unconjugated sKLH were exposed to increasing subcutaneous doses of fentanyl. Vaccination with F-sKLH shifted the dose-response curves to the right for both fentanyl-induced antinociception and respiratory depression. Naloxone reversed fentanyl effects in both groups, showing that its ability to reverse respiratory depression was preserved. These data demonstrate preclinical selectivity and efficacy of a fentanyl vaccine and suggest that vaccines may offer a therapeutic option in reducing fentanyl-induced side effects.


Assuntos
Analgésicos Opioides/antagonistas & inibidores , Analgésicos Opioides/metabolismo , Fentanila/antagonistas & inibidores , Fentanila/metabolismo , Vacinas/farmacologia , Analgésicos Opioides/toxicidade , Animais , Bradicardia/sangue , Bradicardia/induzido quimicamente , Bradicardia/prevenção & controle , Fentanila/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/sangue , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/prevenção & controle , Vacinas/uso terapêutico
19.
Drug Alcohol Depend ; 190: 62-71, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981943

RESUMO

BACKGROUND: Opioid overdose deaths have continued to rise in Tennessee (TN) with fentanyl emerging as a major contributor. Current data are needed to identify at-risk populations to guide prevention strategies. We conducted a large statewide observational study among TN adult decedents (2013-2016) to evaluate the association of sociodemographic factors and prescribing patterns with opioid overdose deaths. METHODS: Among drug overdose decedents identified using death certificate data (n = 5483), we used logistic regression to estimate adjusted odds ratios and 95% confidence intervals for characteristics associated with prescription opioid (PO) (excluding fentanyl), fentanyl, and heroin alone overdoses. Among decedents linked to TN's Prescription Drug Monitoring Database using deterministic algorithms, we obtained prescription history in the year before death (n = 3971), which was evaluated by type of overdose using descriptive statistics. RESULTS: Younger, non-White decedents had lower odds of PO overdose, while females and benzodiazepines as a contributing cause were associated with increased odds of PO overdose. Younger age, Non-Hispanic Black race/ethnicity, greater than high school education, and cocaine/other stimulants as a contributing cause were associated with increased odds of fentanyl or heroin overdoses. Over 55% of PO, 39.2% of fentanyl, and 20.7% of heroin overdoses had an active opioid prescription at death. For PO, fentanyl, and heroin decedents, respectively, 46.0%, 30.5%, and 26.2% had an active prescription for benzodiazepines at death. CONCLUSIONS: Prescription opioid overdose deaths were associated with different sociodemographic profiles and prescribing history compared to fentanyl and heroin overdose deaths in TN. Data can guide prevention strategies to reduce opioid overdose mortality.


Assuntos
Analgésicos Opioides/toxicidade , Interpretação Estatística de Dados , Overdose de Drogas/economia , Overdose de Drogas/mortalidade , Prescrições de Medicamentos , Detecção do Abuso de Substâncias/métodos , Adolescente , Adulto , Idoso , Benzodiazepinas/toxicidade , Atestado de Óbito , Overdose de Drogas/diagnóstico , Grupos Étnicos , Feminino , Fentanila/toxicidade , Heroína/toxicidade , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Fatores de Risco , Fatores Socioeconômicos , Tennessee/epidemiologia , Adulto Jovem
20.
Curr Pharm Biotechnol ; 19(2): 113-123, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29621965

RESUMO

BACKGROUND: Synthetic opioids are compounds that were created to act on the opioid receptors. Novel synthetic opioids include various analogs of fentanyl (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, furanylfentanyl, 4-fluorobutyrylfentanyl or ocfentanil) and newly emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. In the last years, these drugs have rapidly emerged on the recreational drug market, and their abuse has been increasing worldwide. Due to the high potency and the low dose required to produce desired effects, the risk of overdose for these compounds including severe health implications, is quite high. Several fatal intoxication cases related to the abuse of synthetic opioids have recently been reported in the literature. CONCLUSION: As a consequence, the detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and distribution in body fluids. We overviewed the analytical approaches for the investigation of synthetic opioids in postmortem samples reported in the literature, with special emphasis given to cases of lethal intoxication.


Assuntos
Analgésicos Opioides/análise , Analgésicos Opioides/toxicidade , Overdose de Drogas/mortalidade , Overdose de Drogas/patologia , Drogas Ilícitas/análise , Drogas Ilícitas/toxicidade , Benzamidas/análise , Benzamidas/toxicidade , Fentanila/análogos & derivados , Fentanila/análise , Fentanila/toxicidade , Humanos , Piperidinas/análise , Piperidinas/toxicidade
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