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Eutectic mixtures can be formed by adding drugs other than nicotine (DOTNs) to nicotine‐based e‐liquids in electronic cigarettes (e‐cigarettes). Thus, the interaction between nicotine e‐liquids and DOTNs must be evaluated. Presented is the change in e‐cigarette aerosolization of nicotine and methadone alone versus a 1:1 nicotine:methadone mixture to evaluate the possible formation of a eutectic mixture that can result in an increase of drug delivery. E‐liquids were prepared in‐house using 1:1 propylene glycol (PG):vegetable glycerin (VG) as a base plus nicotine, methadone hydrochloride, or 1:1 nicotine:methadone hydrochloride. The e‐liquids were aerosolized via an automated vaping machine using parameters adopted from the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) E‐cigarette Task Force method. Drug recovery was determined by capturing the aerosol from 15 puffs generated by the e‐cigarette. Concentrations of nicotine and methadone aerosolized were determined by gas chromatography–mass spectrometry using nicotine (n = 3), methadone (n = 3), and combined nicotine/methadone e‐liquids (n = 3), each prepared in‐house at 12 mg/ml. The concentration of nicotine and methadone in 15 puffs of the single drug e‐liquids were determined to be 1.60 ± 0.20 and 2.67 ± 0.12 mg, respectively. The concentration of nicotine and methadone in 15 puffs of the multidrug e‐liquid were determined to be 3.66 ± 0.49 and 3.65 ± 0.10 mg, respectively. The single nicotine and methadone e‐liquids had recoveries of 70 ± 0.1% and 84 ± 0.1%, respectively. In the 1:1 mixture, the recovery of both drugs increased. The development of a eutectic mixture can promote aerosolization of the drug and deliver a greater dose to the user. [ABSTRACT FROM AUTHOR]

Rationale: Natural plant products have been used to promote health, prevent sickness, and treat various ailments. These products often consist of leaves, flowers, bark, roots, seeds, and/or other parts of the plant. Many of the pharmacologically active constituents of these products are known, but the pharmacology of these constituents may not be fully elucidated. Natural plant-based products are also available in various forms other than the raw plant material. A wide array of commercial products such as capsules, powders, extracts, and electronic cigarette (e-cigarette) electronic liquids (e-liquids) are readily available and can be purchased from various outlets, both store-based retailers and online. Newer e-cigarettes are often advertised as "heat not burn" and are used for "vaping" various forms of extracts including "waxes" and "dabs" and raw plant material. Methods: A single manufacturer was found online selling "24 different herbs" in powders, extracts, or e-liquids. These were advertised as "legal in the USA" and each product listed multiple effects. Eight e-liquids, six extracts (resins), and four powders from eight different "herbs," namely African dream, areca nut, blue lotus, damiana, kra thum na, kra thum kok, klip dagga, and wild lettuce, were purchased. An advertisement for these products stated, "Most people use the leaves, powder or resin in vaporizers." Direct analysis in real time AccuTOF™ mass spectrometry (DART-MS) was used to identify the psychoactive components in the natural products. Results: The psychoactive compounds that were identified in only two of the eight e-liquids, three of the five resins, and three of the four powders were arecaidine, arecoline, coumarin, entadamide, mitragynine, 7-hydroxymitragynine, and nuciferine. Conclusions: Psychoactive and potentially harmful substances were present in the powders and resins of the natural products. The newer types of e-cigarettes made for consuming natural products may increase their abuse potential. [ABSTRACT FROM AUTHOR]

Background: Complex interactions between environmental and genetic factors influence the risk of developing alcohol use disorder (AUD) in humans. To date, studies of the impact of environment on AUD risk have primarily focused on psychological characteristics or on the effects of developmental exposure to ethanol (EtOH). We recently observed that modifying levels of the long-chain ɷ-3 (LC ɷ-3) fatty acid, eicosapentaenoic acid (EPA), alters acute physiological responses to EtOH in Caenorhabditis elegans. Because mammals derive x-3 fatty acids from their diet, here we asked if manipulating dietary levels of LC ɷ-3 fatty acids can affect EtOH-responsive behaviors in mice. Methods: We used 2 well-characterized inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), which differ in their responses to EtOH. Age-matched young adult male mice were maintained on isocaloric diets that differed only by being enriched or depleted in LC ɷ-3 fatty acids. Animals were subsequently tested for acute EtOH sensitivity (locomotor activation and sedation), voluntary consumption, and metabolism. Fat deposition was also determined. Results: We found that dietary levels of LC ɷ-3s altered EtOH sensitivity and consumption in a genotype-specific manner. Both B6 and D2 animals fed high LC ɷ-3 diets demonstrated lower EtOH-induced locomotor stimulation than those fed low LC ɷ-3 diets. EtOH sedation and EtOH metabolism were greater in D2, but not B6 mice on the high LC ɷ-3 diet. Conversely, LC ɷ-3 dietary manipulation altered EtOH consumption in B6, but not in D2 mice. B6 mice on a high LC ɷ-3 diet consumed more EtOH in a 2-bottle choice intermittent access model than B6 mice on a low LC ɷ-3 diet. Conclusions: Because EtOH sensitivity is predictive of risk of developing AUD in humans, our data indicate that dietary LC ɷ-3 levels should be evaluated for their impact on AUD risk in humans. Further, these studies indicate that genetic background can interact with fatty acids in the diet to significantly alter EtOH-responsive behaviors. [ABSTRACT FROM AUTHOR]

Personal battery-powered vaporizers or electronic cigarettes were developed as an alternative to traditional cigarettes. The modern electronic cigarettes were patented in 2004 by Hon Lik in China. In May 2016, the US Food and Drug Administration (FDA) imposed regulatory statutes on e-cigarettes and their liquid formulations (e-liquids); prior to that, they were unregulated. E-liquids are typically composed of propylene glycol and/or glycerin, flavouring component(s), and active ingredient(s), such as nicotine. Fifty-six commercially available e-liquids, purchased from various sources, contained a variety of flavours and active ingredients. A headspace gas chromatography with flame ionization detector (HS-GC-FID) method was used to analyze these e-liquids for volatiles content. Only one of the e-liquids listed ethanol as a component. The chromatographic separation of volatiles was performed on a Restek BAC-1 column. A linear calibration was generated for ethanol with limits of detection and quantification (LOD/LOQ) of 0.05 mg/mL. Ethanol concentrations in the 56 e-liquids ranged from none detected to 206 mg/mL. The ethanol determined in these products may have been used in flavourants or a solvent; the reason for inclusion cannot be fully ascertained. The implications of vaporizing ethanol as an e-liquid component are unknown. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Pre-clinical drug discrimination procedures are useful for interrogating structure-activity relationships of abuse-related drug effects; however, in vivo structure-activity relationship comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP or methcathinone (methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest that hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects. [ABSTRACT FROM AUTHOR]

In recent years, a large number of designer drugs sold as 'Bath Salts' have appeared on the market. In July of 2011, Raving Dragon Novelty Bath Salts was obtained over the Internet. This product became unavailable in October of that year coinciding with the DEA issuing a temporarily schedule of mephedrone, methylone, and MDPV. Four months later in February of 2012, a new product was released from the same company under the new name Raving Dragon Voodoo Dust. The contents of both products were identified using spectroscopy methods: nuclear magnetic resonance, infrared, UV-visible, tandem mass spectrometry, and high-resolution time-of-flight mass spectrometry. It was determined that Raving Dragon Novelty Bath Salts contained methylone. The replacement product Raving Dragon Voodoo Dust contained the unscheduled drug pentedrone. The Raving Dragon brand of products illustrates the rapid change of ingredients in these products to circumvent laws restricting availability, distribution, and use. [ABSTRACT FROM AUTHOR]

We present a case of 4-bromo-2,5-dimethoxy-N-[(2-methoxyphenyl)methyl]-benzeneethanamine (25B-NBOMe), an N-benzyl phenethylamines derivative, intoxication and a high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method for detection and quantification of 25B-NBOMe. A 19-year-old male was found unresponsive with generalized grand mal seizure activity. On the second day of hospitalization, a friend admitted that the patient used 'some unknown drug' called 25B. Serum and urine collected were sent to the Virginia Commonwealth University Medical Center Toxicology Laboratory for analysis. An HPLC-MS/MS method for the identification and quantification of 25B-NBOMe using 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe) as the internal standard (ISTD) was developed. As this is a novel, single-case presentation, an assay validation was performed prior to testing to ensure the reliability of the analytical results. The serum and urine specimens were determined to contain 180 pg/ml and1900 pg/ml of 25B-NBOMe, respectively. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT 2CC-NBOMe {4-chloro-2,5-dimethoxyphenethyl- N-[(2-methoxyphenyl) methyl] ethanamine} and 25I-NBOMe {2-(4-iodo-2,5-dimethoxyphenyl)- N-[(2-methoxyphenyl) methyl] ethanamine} are of a class of N-benzyl phenethylamine derivatives whose synthesis was first reported in the scientific literature in 2011. Recent reports from 'personal drug experience websites' and in the popular press indicate these drugs are the latest in a series of designer 'Bath Salt' drugs of abuse. The presented high-performance liquid chromatography triple quadrupole mass spectrometry (HPLC/MS/MS) method was developed for the detection and quantification of 2CC-NBOMe and 25I-NBOMe in serum of intoxicated emergency department patients. The assay applies 2- (2, 5- dimethoxyphenyl)- N- (2- methoxybenzyl) ethanamine (25H-NBOMe) as the internal standard. Samples were extracted using solid-phase extraction columns. The chromatographic separation was performed on a Luna 3 µ C8(2) 100 Å, 100 × 2.0 mm, column. Detection was accomplished by multiple-reaction monitoring via an electrospray ionization source operating in the positive ionization mode. The calibration curves were linear over the investigated concentration range, 30-2000 pg/mL, with a lower limit of detection of 10 pg/mL for both 2CC-NBOMe and 25I-NBOMe. The method proved suitable for serum clinical toxicology testing. Two severely intoxicated emergency department patients were determined to have serum concentrations of 250 and 2780 pg/mL of 25I-NBOMe using the presented method. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT The disposition of the cannabimimetic naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in mice following inhalation of the smoke of the herbal incense product (HIP) 'Buzz' is presented. A high-pressure liquid chromatography with electrospray ionization triple quadrupole mass spectrometer (HPLC/MS/MS) method was validated for the analysis of JWH-018 in the specimens using deuterated Δ9-tetrahydrocannabinol (d3-THC) as the internal standard. JWH-018 was isolated by cold acetonitrile liquid-liquid extraction. Chromatographic separation was performed on a Zorbaz eclipse XDB-C18 column. The assay was linear from 1 to 1000 ng/mL. Six C57BL6 mice were sacrificed 20 min after exposure to the smoke of 200 mg 'Buzz' containing 5.4% JWH-018. Specimen concentrations of JWH-018 were: blood, 54-166 ng/mL (mean 82 ± 42 ng/mL); brain, 316-708 ng/g (mean 510 ± 166 ng/g); and liver, 1370-3220 ng/mL (mean 1990 ± 752 ng/mL). The mean blood to brain ratio for JWH-018 was 6.8 and ranged from 4.2 to 10.9. After exposure, the responses of the mice were consistent with cannabinoid receptor type 1 activity: body temperatures dropped 7.3 ± 1.1 °C, and catalepsy, hyperreflexia, straub tail and ptosis were observed. The brain concentrations and physiological responses are consistent with the hypothesis that the behavioral effects of 'Buzz' are attributable to JWH-018. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study tested the hypothesis that homocysteine (Hcys)-induced ceramide production stimulates lipid rafts (LRs) clustering on the membrane of glomerular endothelial cells (GECs) to form redox signalling platforms by aggregation and activation of NADPH oxidase subunits and thereby enhances superoxide (O2.−) production, leading to glomerular endothelial dysfunction and ultimate injury or sclerosis. Using confocal microscopy, we first demonstrated a co-localization of LR clusters with NADPH oxidase subunits, gp91 phox and p47 phox in the GECs membrane upon Hcys stimulation. Immunoblot analysis of floated detergent-resistant membrane fractions found that in LR fractions NADPH oxidase subunits gp91 phox and p47 phox are enriched and that the activity of this enzyme dramatically increased. We also examined the effect of elevated Hcys on the cell monolayer permeability in GECs. It was found that Hcys significantly increased GEC permeability, which was blocked by inhibition of LR redox signalling platform formation. Finally, we found that Hcys-induced enhancement of GEC permeability is associated with the regulation of microtubule stability through these LR-redox platforms. It is concluded that the early injurious effect of Hcys on the glomerular endothelium is associated with the formation of redox signalling platforms via LR clustering, which may lead to increases in glomerular permeability by disruption of microtubule network in GECs. [ABSTRACT FROM AUTHOR]

Carbenoxolone is a derivative of glycyrrhetinic acid found in the root of Glycyrrhiza glabra, colloquially known as licorice. It has been used as a treatment for peptic and oral ulcers. In recent years, carbenoxolone has been utilized in basic research for its ability to block gap junctional communication. Better understanding the distribution of carbenoxolone after systemic administration can lead to a better understanding of its potential sites of action. Presented is an ultra high‐performance liquid chromatography tandem mass spectrometer (UHPLC–MS/MS) method for the identification and quantification of carbenoxolone in mouse blood and brain tissue. Twenty mice were injected intraperitoneally with 25 mg/kg carbenoxolone and brain tissue and blood were collected for analysis. Blood concentrations (mean ± SD) at 15, 30, 60 and 120 min were determined to be (n = 5) 5394 ± 778, 2636 ± 836, 1564 ± 541 and 846 ± 252 ng/mL, respectively. Brain concentrations (mean ± SD) at 15, 30, 60 and 120 mins were determined to be (n = 5) 171 ± 62, 102 ± 35, 55 ± 10 and 27 ± 9 ng/g, respectively. The analysis of these specimens at the four different time points resulted in blood and brain half‐lives in mice of ~43 and 41 min, respectively. The UHPLC–MS/MS method was determined to be sensitive and robust for quantification of carbenoxolone. [ABSTRACT FROM AUTHOR]

The article presents a case study of the toxicity of dimethoxyphenyl-N-[(2-methoxyphenyl)methyl] ethanamine derivatives (NBOMes), a novel class of potent synthetic hallucinogens, which became available as recreational drugs. It cites the case of a 16-year-old male presented to the emergency department after ingesting what he believed to be LSD (lysergic acid diethylamide) on red blotting paper. It reminds clinicians to be aware of NBOMes, which can cause prolonged agitation and hallucinations.

The present study tested the hypothesis that homocysteine (Hcys)-induced ceramide production stimulates lipid rafts (LRs) clustering on the membrane of glomerular endothelial cells (GECs) to form redox signalling platforms by aggregation and activation of NADPH oxidase subunits and thereby enhances superoxide (O2*-) production, leading to glomerular endothelial dysfunction and ultimate injury or sclerosis. Using confocal microscopy, we first demonstrated a co-localization of LR clusters with NADPH oxidase subunits, gp91(phox) and p47(phox) in the GECs membrane upon Hcys stimulation. Immunoblot analysis of floated detergent-resistant membrane fractions found that in LR fractions NADPH oxidase subunits gp91(phox) and p47(phox) are enriched and that the activity of this enzyme dramatically increased. We also examined the effect of elevated Hcys on the cell monolayer permeability in GECs. It was found that Hcys significantly increased GEC permeability, which was blocked by inhibition of LR redox signalling platform formation. Finally, we found that Hcys-induced enhancement of GEC permeability is associated with the regulation of microtubule stability through these LR-redox platforms. It is concluded that the early injurious effect of Hcys on the glomerular endothelium is associated with the formation of redox signalling platforms via LR clustering, which may lead to increases in glomerular permeability by disruption of microtubule network in GECs.