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The Journal of Emergency Medicine Aug 2020Emergency department (ED) recidivism and the use of amphetamine and associated derivatives such as methamphetamine and MDMA (MAE), are intersecting public health...
BACKGROUND
Emergency department (ED) recidivism and the use of amphetamine and associated derivatives such as methamphetamine and MDMA (MAE), are intersecting public health concerns.
OBJECTIVE
This study aims to determine the frequency of ED recidivism of patients who use MAE and associated factors.
METHODS
The study was a retrospective 6-year electronic medical record review of patients with MAE-positive toxicology screens and single and multiple ED visits in the span of 12 months.
RESULTS
There were 7844 ED visits by 5568 MAE-positive patients. Average age was 42 ± 13 years. The majority were male (65%), white (46%), tobacco smokers (55%), and in the psychiatric discharge diagnostic-related group (41%), followed by blunt trauma (20%). Admission rate was 35%, with another 17% transferred to inpatient psychiatric treatment facilities. Occasional (2-5 visits/year), heavy (6-11 visits/year), and super users (≥12 visits/year) altogether accounted for 20% of patients and 43% of visits. Heavy and super users combined represented 2% of patients and 10% of visits, with significant differences for race/ethnicity, health insurance, tobacco smoking, and psychiatric/cardiovascular/trauma discharge diagnostic-related groups. Heavy and super users were less likely to be admitted and more likely to be discharged to an inpatient psychiatric treatment facility. Regression analysis revealed racial/ethnic differences, female gender, and tobacco smoking to be associated with super and heavy use. Heavy users were more likely to have cardiovascular-related discharge diagnoses.
CONCLUSIONS
The prevalence of ED recidivism in patients who use MAE is similar to published ranges for general ED users. Significant differences in demographics, discharge diagnoses, insurance, smoking, and disposition exist between nonfrequent and frequent ED users.
Topics: Adult; Amphetamine; Emergency Service, Hospital; Female; Humans; Male; Methamphetamine; Middle Aged; N-Methyl-3,4-methylenedioxyamphetamine; Recidivism; Retrospective Studies
PubMed: 32546441
DOI: 10.1016/j.jemermed.2020.04.051 -
Journal of Analytical Toxicology Jan 2023"Designer" benzodiazepines (DBZDs) are becoming increasingly available in Europe, with the European Monitoring Centre of Drugs and Drug Addiction currently monitoring...
"Designer" benzodiazepines (DBZDs) are becoming increasingly available in Europe, with the European Monitoring Centre of Drugs and Drug Addiction currently monitoring ∼30 new benzodiazepines. The following driving under the influence of drug (DUID) case describes the oral fluid (OF) and blood concentrations, as well as the observed effects after the combined use of stimulants and flubromazepam. Both OF, collected via the Intercept i2 collector (Immunalysis, Pomona, CA, USA), and blood (collected in containers with various stabilizers) were screened using a liquid chromatographic (LC) time-of-flight (TOF) mass spectrometric (MS-MS) method. In addition, various LC-MS-MS methods in multi-reaction monitoring mode were applied for confirmation and quantification. The OF and blood samples were taken 2 h 25 min and 9 h 19 min after the accident, respectively. OF contained 789 ng/mL amphetamine, 5,173 ng/mL MDMA, 168 ng/mL benzoylecgonine, 492 ng/mL cocaine, 134 ng/mL 4-methylmethcathinone (4-MMC) and traces of flubromazepam (less than limit of quantification (LLOQ); 2 ng/mL). The sodium-fluoride blood samples contained 19 ng/mL amphetamine, 284 ng/mL MDMA, 20 ng/mL MDA, 38 ng/mL benzoylecgonine, 4 ng/mL methylecgonine, 161 ng/mL flubromazepam and traces of 4-MMC (
Topics: Male; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Central Nervous System Stimulants; Amphetamine; Benzodiazepines; Substance Abuse Detection
PubMed: 36107733
DOI: 10.1093/jat/bkac071 -
The Journal of Pharmacology and... May 2021Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume...
Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were = 475 (11), = 4.01 (5.4), = 50.6 (93), and = 47.8 (16), and efficacies (%RSE within parentheses) were = 0.944 (1.7), = 1.00 (1.3), = 0.195 (9.9), and = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.
Topics: Animals; Biomarkers, Pharmacological; Blood Pressure; Cardiotoxicity; Cardiovascular Agents; Heart Rate; Ivabradine; Male; Phenethylamines; Pyridazines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides
PubMed: 33648939
DOI: 10.1124/jpet.120.000348 -
Addiction Biology Sep 2022N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT agonists containing substances emerging on the illicit drug market as a replacement for...
N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.
Topics: Animals; Body Temperature Regulation; Dose-Response Relationship, Drug; Hallucinogens; Phenethylamines; Rats; Rats, Wistar
PubMed: 36001433
DOI: 10.1111/adb.13216 -
Fa Yi Xue Za Zhi Feb 2024To investigate the toxicokinetic differences of 3,4-methylenedioxy--methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after...
OBJECTIVES
To investigate the toxicokinetic differences of 3,4-methylenedioxy--methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA.
METHODS
A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis.
RESULTS
In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: =10.362, =0.974 6; =7.397 3, =0.961 5 (: injection time; : concentration ratio of MDMA to MDA in plasma).
CONCLUSIONS
The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.
Topics: Rats; Animals; Amphetamine; N-Methyl-3,4-methylenedioxyamphetamine; 3,4-Methylenedioxyamphetamine; Toxicokinetics; Saline Solution; Amphetamines
PubMed: 38500459
DOI: 10.12116/j.issn.1004-5619.2022.320201 -
European Journal of Pharmacology Sep 2019Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with...
Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with undefined pharmacological activity. We investigated whether substances that are contained in commercially available athletic multiple-ingredient preworkout supplements exert amphetamine-type activity at norepinephrine, dopamine, and serotonin transporters (NET, DAT, and SERT, respectively). We assessed the in vitro monoamine transporter inhibition potencies of the substances using human embryonic kidney 293 cells that expressed the human NET, DAT, and SERT. The phenethylamines β-phenethylamine, N-methylphenethylamine, β-methylphenethylamine, N-benzylphenethylamine, N-methyl-β-methylphenethylamine, and methylsynephrine inhibited the NET and less potently the DAT similarly to D-amphetamine. β-phenethylamine was the most potent, with IC values of 0.05 and 1.8 μM at the NET and DAT, respectively. These IC values were comparable to D-amphetamine (IC = 0.09 and 1.3 μM, respectively). The alkylamines 1,3-dimethylbutylamine and 1,3-dimethylamylamine blocked the NET but not the DAT. Most of the phenethylamines interacted with trace amine-associated receptor 1, serotonin 5-hydroxytryptamine-1A receptor, and adrenergic α and α receptors at submicromolar concentrations. None of the compounds blocked the SERT. In conclusion, products that are used by athletes may contain substances with mainly noradrenergic amphetamine-type properties.
Topics: Biogenic Monoamines; Biological Transport; Catecholamine Plasma Membrane Transport Proteins; Dietary Supplements; Exercise; HEK293 Cells; Humans; Performance-Enhancing Substances; Phenethylamines
PubMed: 31265842
DOI: 10.1016/j.ejphar.2019.172515 -
ACS Chemical Neuroscience Aug 2023Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT) as their main pharmacological action. Despite their relevance, the...
Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and -benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGα to the 5-HT, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC and values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGα- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).
Topics: Serotonin; Receptor, Serotonin, 5-HT2A; Molecular Docking Simulation; Hallucinogens; Phenethylamines; Serotonin 5-HT2 Receptor Agonists
PubMed: 37474114
DOI: 10.1021/acschemneuro.3c00267 -
European Neuropsychopharmacology : the... Jun 20223,4-methylenedioxyamphetamine (MDA) is a psychoactive compound chemically related to the entactogen MDMA. MDA shares some of the entactogenic effects of MDMA but also...
3,4-methylenedioxyamphetamine (MDA) is a psychoactive compound chemically related to the entactogen MDMA. MDA shares some of the entactogenic effects of MDMA but also exerts stimulant effects and psychedelic properties at higher doses. Here, we examined the pharmacological properties of MDA analogs and related amphetamine-based compounds detected in street drug samples or in sport supplements. We examined the key pharmacological mechanisms including monoamine uptake inhibition and release using human embryonic kidney 293 cells stably transfected with the respective human transporters. Additionally, we assessed monoamine transporter and receptor binding and activation properties. MDA, its fluorinated analogs, as well as the α-ethyl containing BDB and the dimeric amphetamine DPIA inhibited NET with the greatest potency and preferentially inhibited 5-HT vs. dopamine uptake. The β‑methoxy MDA analog 3C-BOH and the amphetamine-based N,α-DEPEA inhibited NET and preferentially inhibited dopamine vs. 5-HT uptake. The test drugs mediated efflux of at least one monoamine with the exception of DPIA. Most compounds bound to 5-HT and 5-HT receptors (K ≤ 10 µM) and several substances activated the 5-HT and 5-HT receptor as partial or full agonists. Furthermore, several compounds interacted with adrenergic receptors and the trace amine-associated receptor 1 (TAAR1) in the micromolar range. The pharmacological profiles of some fluorinated and nonfluorinated MDA analogs resemble the profile of MDMA. In contrast, 3C-BOH and N,α-DEPEA displayed more pronounced dopaminergic activity similar to amphetamine. Pharmacokinetics and pharmacodynamics studies are necessary to better establish the risks and therapeutic potential of the tested drugs.
Topics: 3,4-Methylenedioxyamphetamine; Amphetamine; Carrier Proteins; Dopamine; Humans; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Serotonin
PubMed: 35378384
DOI: 10.1016/j.euroneuro.2022.03.006 -
Forensic Science International Nov 2022In this study, fluorine-19 nuclear magnetic resonance spectroscopy (F NMR) served as a highly specific tool for identification of fluorinated new psychoactive substances...
In this study, fluorine-19 nuclear magnetic resonance spectroscopy (F NMR) served as a highly specific tool for identification of fluorinated new psychoactive substances (NPS) as well as a suitable analytical method for the accurate quantification of fluorinated NPS in different seized samples. In the first part of the study, F NMR spectroscopy of a number of different fluorinated NPS, including 51 synthetic cannabinoids, 8 synthetic cathinones, 7 phenethylamines, 8 fentanyl analogues, and 9 other types of compounds was conducted. The chemical shifts and multiplet of the primary fluorides (RCHF), fluorobenzenes (ortho-ArF, meta-ArF, and para-ArF), and trifluoromethylbenzenes (ArCF) were discussed in detail to illustrate the role of F signals as special fingerprints in assisting the structure identification of fluorine-containing NPS. To the best of our knowledge, this study is the largest evaluation of fluorinated NPS compounds by F NMR. The second part of this study dealt with the problems encountered in the F quantification procedure and the criteria to be considered for successful quantification by F NMR. General high field (HF)- and low field (LF)- F qNMR methods for the quantification of fluorinated NPS were established after the thorough discussion of NMR spectrum acquisition and processing parameters such as: transmitter frequency offset (O1P), spin-lattice relaxation time (T), and different baseline correction methods. The limit of quantifications (LOQs) for HF-F qNMR varied between 0.1 mg/mL and 0.2 mg/mL, and for LF-F qNMR varied between 1.0 mg/mL and 2.0 mg/mL. The limit of detections (LODs) for HF-F qNMR varied between 0.03 mg/mL and 0.06 mg/mL, and for LF-F qNMR varied between 0.3 mg/mL and 0.6 mg/mL. Finally, the developed methods were applied for the quantification of fluorinated-NPS in seventeen herbal blends, e-liquid, tablet, and powder NPS seizures.
Topics: Cannabinoids; Central Nervous System Agents; Fentanyl; Fluorides; Fluorine; Fluorobenzenes; Magnetic Resonance Spectroscopy; Phenethylamines; Powders
PubMed: 36152449
DOI: 10.1016/j.forsciint.2022.111450 -
Analytical Methods : Advancing Methods... Jul 2022Reliable and feasible tools for detecting ()-methamphetamine [()-MAP] and ()-amphetamine [()-AP] are required for regulating their illicit circulation. Antibodies that...
Reliable and feasible tools for detecting ()-methamphetamine [()-MAP] and ()-amphetamine [()-AP] are required for regulating their illicit circulation. Antibodies that react equally to these stimulants are desirable for this purpose, but have been difficult to generate because of the crucial difference between their characteristic structures: ., -methylamino (MAP) and amino (AP) groups. Furthermore, their small molecular masses ( < 150) have hampered the generation of high-affinity antibodies. To overcome these problems, we converted ()-MAP and -AP into their 2-(trimethylsilyl)ethyl carbamate forms, Teoc-()-MAP and -AP, respectively, as surrogate analytes. The Teoc-derivatization not only increases their molecular masses, but also masks their structural differences. We generated a novel monoclonal antibody that showed a satisfactory affinity to Teoc-()-MAP residues ( = 13 nM as the IgG form) and developed a competitive enzyme-linked immunosorbent assay (ELISA) using microplates containing immobilized Teoc-()-MAP residues. Almost overlapping dose-response curves were obtained for Teoc-()-MAP and -AP, with the limit of detection of 0.078 and 0.10 ng per assay, respectively. A fixed amount of test powder sample (1 mg) was derivatized with Teoc--succinimidyl for 5 min, and subjected to ELISA using Teoc-()-MAP as the calibration standard. Under this protocol, ()-MAP and -AP were converted to their Teoc derivatives with 30% and 34% yield, respectively, determined using ELISA as "Teoc-()-MAP equivalent," being distinguished from the derivatization products of ()-MAP, ()-AP, ephedrine, ()-methylenedioxymethamphetamine, tyramine, dopamine, and β-alanine. This ELISA detected as little as 10 μg of ()-MAP and -AP, and ()-MAP in urine obtained from ()-MAP-administered rats. Immunochromatography devices were also developed using gold nanoparticles coated with the monoclonal antibody, with which 0.10 mg of ()-MAP and -AP was detected by the naked eye. We conclude that the present derivatization-assisted immunoassays may be useful for the detection of ()-MAP and/or -AP in early stage screening of suspicious substances.
Topics: Amphetamine; Animals; Antibodies, Monoclonal; Enzyme-Linked Immunosorbent Assay; Gold; Metal Nanoparticles; Methamphetamine; Rats
PubMed: 35785801
DOI: 10.1039/d2ay00940d