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Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT inhibitor) or methylone (a DAT substrate) into the caudate putamen of male Sprague-Dawley rats. Dialysate samples were collected prior to and post drug administration, and temporal changes in dopamine concentration were quantified using HPLC-EC methods. Methylone elicited a 200% increase and MDPV a 470% increase in dopamine levels at the 10 min time point. The findings demonstrate that in vivo retrodialysis can be used to evaluate the effects of SPCs on neurotransmission in the brain. [ABSTRACT FROM AUTHOR]

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake). [ABSTRACT FROM AUTHOR]

Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT inhibitor) or methylone (a DAT substrate) into the caudate putamen of male Sprague-Dawley rats. Dialysate samples were collected prior to and post drug administration, and temporal changes in dopamine concentration were quantified using HPLC-EC methods. Methylone elicited a 200% increase and MDPV a 470% increase in dopamine levels at the 10 min time point. The findings demonstrate that in vivo retrodialysis can be used to evaluate the effects of SPCs on neurotransmission in the brain.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins—brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)—was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxypyrovalerone (MDPV) is a widely studied synthetic cathinone heterocycle mainly concerning its psychoactive effects. It is a chiral molecule and one of the most abused new psychoactive substances worldwide. Enantioselectivity studies for MDPV are still scarce and the extent to which it crosses the intestinal membrane is still unknown. Herein, an in vitro permeability study was performed to evaluate the passage of the enantiomers of MDPV across the Caco-2 monolayer. To detect and quantify MDPV, a UHPLC-UV method was developed and validated. Acceptable values within the recommended limits were obtained for all evaluated parameters (specificity, linearity, accuracy, limit of detection (LOD), limit of quantification (LOQ) and precision). The enantiomers of MDPV were found to be highly permeable across the Caco-2 monolayer, which can indicate a high intestinal permeability. Enantioselectivity was observed for the Papp values in the basolateral (BL) to apical (AP) direction. Furthermore, efflux ratios are indicative of efflux through a facilitated diffusion mechanism. To the best of our knowledge, determination of the permeability of MDPV across the intestinal epithelial cell monolayer is presented here for the first time. [ABSTRACT FROM AUTHOR]

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers’ stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins—brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)—was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.

Abstract Background Waterfowl parvoviruses, including goose parvovirus (GPV) and Muscovy duck parvovirus (MDPV), can cause seriously diseases in geese and ducks. Developing a fast and precise diagnosis assay for these two parvoviruses is particularly important. Results A duplex SYBR Green I-based quantitative real-time PCR assay was developed for the simultaneous detection and differentiation of GPV and MDPV. The assay yielded melting curves with specific single peak (Tm = 87.3 ± 0.26 °C or Tm = 85.4 ± 0.23 °C) when GPV or MDPV was evaluated, respectively. When both parvoviruses were assessed in one reaction, melting curves with specific double peaks were yielded. Conclusion This duplex quantitative RT-PCR can be used to rapid identify of GPV and MDPV in field cases and artificial trials, which make it a powerful tool for diagnosing, preventing and controlling waterfowl parvovirus infections.

[West J Emerg Med. 2012;13(1):58–62.]

Abstract Background Muscovy duck parvovirus (MDPV) causes high mortality and morbidity in Muscovy ducks, with the pathogenesis of the virus still unknown in many respects. Specific MDPV detection is often rife with false positive results because of high identity at the genomic nucleotide level and antigenic similarity with goose parvovirus (GPV). The objective of this study was to develop a sensitive, highly specific, and repeatable TaqMan-based real-time PCR (qPCR) assay for facilitating the molecular detection of MDPV. Results The specific primers and probe were designed based on the conserved regions within MDPVs, but there was a variation in GPVs of the nonstructural (NS) genes after genetic comparison. After the optimization of qPCR conditions, the detection limit of this qPCR assay was 29.7 copies/μl. The assay was highly specific for the detection of MDPV, and no cross-reactivity was observed with other non-targeted duck-derived pathogens. Intra- and inter-assay variability was less than 2.21%, means a high degree of repeatability. The diagnostic applicability of the qPCR assay was proven that MDPV-positive can be found in cloacal swabs samples, Muscovy duck embryos and newly hatched Muscovy ducklings. Conclusions Our data provided incidents that MDPV could be possible vertically transmitted from breeder Muscovy ducks to Muscovy ducklings. The developed qPCR assay in the study could be a reliable and specific tool for epidemiological surveillance and pathogenesis studies of MDPV.

Abstract Introduction Pyrovalerone (4‐methyl‐β‐keto‐prolintane) is a synthetic cathinone (beta‐keto‐amphetamine) derivative. Cathinones are a concern as drugs of abuse, as related street drugs such as methylenedioxypyrovalerone have garnered significant attention. The primary mechanism of action of cathinones is to inhibit reuptake transporters (dopamine and norepinephrine) in reward centers of the central nervous system. Methods We measured bioenergetic, behavioral, and molecular responses to pyrovalerone (nM‐µM) in zebrafish to evaluate its potential for neurotoxicity and neurological impairment. Results Pyrovalerone did not induce any mortality in zebrafish larvae over a 3‐ and 24‐hr period; however, seizures were prevalent at the highest dose tested (100 µM). Oxidative phosphorylation was not affected in the embryos, and there was no change in superoxide dismutase 1 expression. Following a 3‐hr treatment to pyrovalerone (1–100 µM), larval zebrafish (6d) showed a dose‐dependent decrease (70%–90%) in total distance moved in a visual motor response (VMR) test. We interrogated potential mechanisms related to the hypoactivity, focusing on the expression of dopamine‐related transcripts as cathinones can modulate the dopamine system. Pyrovalerone decreased the expression levels of dopamine receptor D1 (~60%) in larval zebrafish but did not affect the expression of tyrosine hydroxylase, dopamine active transporter, or any other dopamine receptor subunit examined, suggesting that pyrovalerone may regulate the expression of dopamine receptors in a specific manner. Discussion Further studies using zebrafish are expected to reveal new insight into molecular mechanisms and behavioral responses to cathinone derivates, and zebrafish may be a useful model for understanding the relationship between the dopamine system and bath salts.

3,4-methylenedioxypyrovalerone (MDPV) is a potent pyrovalerone cathinone that is substituted for amphetamines by recreational users. We report a comprehensive and detailed description of the effects of subcutaneous MDPV (1–4 mg/kg) on pharmacokinetics, biodistribution and metabolism, acute effects on thermoregulation under isolated and aggregated conditions, locomotion (open field) and sensory gating (prepulse inhibition, PPI). All studies used male Wistar rats. Pharmacokinetics after single dose of 2 mg/kg MDPV was measured over 6 h in serum, brain and lungs. The biotransformation study recorded 24 h urinary levels of MDPV and its metabolites after 4 mg/kg. The effect of 2 mg/kg and 4 mg/kg on body temperature (°C) was measured over 12 h in group- vs. individually-housed rats. In the open field, locomotion (cm) and its spatial distribution were assessed. In PPI, acoustic startle response (ASR), habituation, and PPI were measured (AVG amplitudes). In behavioural experiments, 1, 2, or 4 mg/kg MDPV was administered 15 or 60 min prior to testing. Thermoregulation and behavioural data were analysed using factorial analysis of variance (ANOVA). Peak concentrations of MDPV in sera, lung and brain tissue were reached in under 30 min. While negligible levels of metabolites were detected in tissues, the major metabolites in urine were demethylenyl-MDPV and demethylenyl-methyl-MDPV at levels three-four times higher than the parent drug. We also established a MDPV brain/serum ratio ~2 lasting for ~120 min, consistent with our behavioural observations of locomotor activation and disrupted spatial distribution of behaviour as well as moderate increases in body temperature (exacerbated in group-housed animals). Finally, 4 mg/kg induced stereotypy in the open field and transiently disrupted PPI. Our findings, along with previous research suggest that MDPV is rapidly absorbed, readily crosses the blood-brain barrier and is excreted primarily as metabolites. MDPV acts as a typical stimulant with modest hyperthermic and psychomimetic properties, consistent with a primarily dopaminergic mechanism of action. Since no specific signs of acute toxicity were observed, even at the highest doses used, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.

3,4-methylenedioxypyrovalerone (MDPV) is a potent pyrovalerone cathinone that is substituted for amphetamines by recreational users. We report a comprehensive and detailed description of the effects of subcutaneous MDPV (1-4 mg/kg) on pharmacokinetics, biodistribution and metabolism, acute effects on thermoregulation under isolated and aggregated conditions, locomotion (open field) and sensory gating (prepulse inhibition, PPI). All studies used male Wistar rats. Pharmacokinetics after single dose of 2mg/kg MDPV was measured over 6 h in serum, brain and lungs. The biotransformation study recorded 24 h urinary levels of MDPV and its metabolites after 4 mg/kg. The effect of 2 mg/kg and 4 mg/kg on body temperature (°C) was measured over 12 h in group- vs. individually-housed rats. In the open field, locomotion (cm) and its spatial distribution were assessed. In PPI, acoustic startle response (ASR), habituation, and PPI were measured (AVG amplitudes). In behavioural experiments, 1, 2, or 4mg/kg MDPV was administered 15 or 60min prior to testing. Thermoregulation and behavioural data were analysed using factorial analysis of variance (ANOVA). Peak concentrations of MDPV in sera, lung and brain tissue were reached in under 30min. While negligible levels of metabolites were detected in tissues, the major metabolites in urine were demethylenyl-MDPV and demethylenyl-methyl-MDPV at levels three-four times higher than the parent drug. We also established a MDPV brain/serum ratio ~2 lasting for ~120min, consistent with our behavioural observations of locomotor activation and disrupted spatial distribution of behaviour as well as moderate increases in body temperature (exacerbated in group-housed animals). Finally, 4 mg/kg induced stereotypy in the open field and transiently disrupted PPI. Our findings, along with previous research suggest that MDPV is rapidly absorbed, readily crosses the blood-brain barrier and is excreted primarily as metabolites. MDPV acts as a typical stimulant with modest hyperthermic and psychomimetic properties, consistent with a primarily dopaminergic mechanism of action. Since no specific signs of acute toxicity were observed, even at the highest doses used, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones. [ABSTRACT FROM AUTHOR]

3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone belonging to the class of α-pyrrolidinophenones that become increasingly popular as a designer psychostimulant. Here, we report a comprehensive collection of MDPV exposure with quantitative serum level confirmation in Germany. During the years 2014-2016, we could proof consumption of MDPV in 23 cases where urine and blood samples were submitted to our laboratory by the police of Lower Saxony. Most of the samples underwent systematic toxicological analysis by gas chromatography-mass spectrometry (GC-MS), where MDPV could be detected in urine and/or serum samples. The determined concentrations of MDPV in serum showed a high variability, ranging from traces (<10ng/mL) up to 576ng/mL with a mean concentration of 118ng/mL and median of 47ng/mL. The majority of MDPV users were men (87%) and the age ranged from 23 to 49 years (mean 35.9, median 37 years). For most of the analytically confirmed MDPV cases we could prove co-consumption of other psychotropic drugs with frequent occurrence of opiates and cannabinoids in 22% of the cases, followed by benzodiazepines and cocaine in 17%. Analysis of urine samples by GC-MS disclosed the presence of MDPV and its metabolites 2'-oxo-MDPV, demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-oxo-MDPV, demethylenyl-methyl-oxo-MDPV and demethylenyl-methyl-N,N-bisdealkyl-MDPV. The metabolite pattern substantiates previous suggestions for principle metabolic pathways of MDPV in humans. [ABSTRACT FROM AUTHOR]

[West J Emerg Med. 2012;13(1):58–62.]

Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10−12 g/L and 1.0 × 10−6 g/L with the limit of detection (LOD) of 1.4 × 10−13 g/L and 2.0 × 10−13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor. [ABSTRACT FROM AUTHOR]

A fast and sensitive methodology has been developed for the evaluation of the 3,4-methylenedioxypyrovalerone (MDPV) consumed. Based on ion mobility spectrometry (IMS), MDPV was directly determined in nasal fluids with a limit of detection (LOD) in the order of 22 ng mL, which corresponds to an absolute amount of 33 ng of MDPV per swab. MDPV was also determined after liquid-liquid microextraction (LLME) in oral fluids to avoid matrix effects, obtaining a LOD value of 4.4 ng mL in oral fluid samples. The IMS spectrum for MDPV exhibited a peak with K = 1.210 ± 0.005 cmV s at a drift time of 14.62 ms, the total analysis time being 4.5 min per oral fluid and 1.5 min per nasal fluid sample. Samples must be analyzed within 24 h following collection and dissolution in 2-propanol, based on the complementary stability studies. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The aim of the present study was to identify the in vitro Phase I and Phase II metabolites of three new psychoactive substances: α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV), and methedrone, using human liver microsomes and human liver cytosol. Accurate-mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry. Six Phase I metabolites of α-PVP were identified, which were formed involving reduction, hydroxylation, and pyrrolidine ring opening reactions. The lactam compound was the major metabolite observed for α-PVP. Two glucuronidated metabolites of α-PVP, not reported in previous in vitro studies, were further identified. MDPV was transformed into 10 Phase I metabolites involving reduction, hydroxylation, and loss of the pyrrolidine ring. Also, six glucuronidated and two sulphated metabolites were detected. The major metabolite of MDPV was the catechol metabolite. Methedrone was transformed into five Phase I metabolites, involving N- and O-demethylation, hydroxylation, and reduction of the ketone group. Three metabolites of methedrone are reported for the first time. In addition, the contribution of individual human CYP enzymes in the formation of the detected metabolites was investigated. [ABSTRACT FROM AUTHOR]

The name `bath salts', for an emerging class of synthetic cathinones, is derived from an attempt to evade prosecution and law enforcement. These are truly illicit drugs that have psychoactive CNS (central nervous system) stimulant effects and they have seen a rise in abuse as recreational drugs in the last few years since first having been seen in Japan in 2006. The ease of synthesis and modification of specific functional groups of the parent cathinone make these drugs particularly difficult to regulate. MDPV (3,4-methylenedioxypyrovalerone) is commonly encountered as its hydrochloride salt (C16H21NO3·HCl), in either the hydrated or the anhydrous forms. This `bath salt' has various names in the US, e.g. `Super Coke', `Cloud Nine', and `Ivory Wave', to name just a few. We report here the structures of two forms of the HCl salt, one as a mixed bromide/chloride salt, C16H22NO3+·0.343Br−·0.657Cl− [systematic name: 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide/chloride (0.343/0.657)], and the other with the H7O3+ cation, as well as the HCl counter-ion [systematic name: hydroxonium 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one dichloride, H7O3+·C16H22NO3+·2Cl−]. This is one of a very few structures (11 to be exact) in which we have a new example of a precisely determined hydroxonium cation. During the course of researching the clandestine manufacture of MDPV, we were surprised by the fact that a common precursor of this illicit stimulant is known to be the fragrant species piperonal, which is present in the fragrances of orchids, most particularly in the case of the vanilla orchid. We found that MDPV can be made by a Grignard reaction of this heliotropin. This may also explain the unexpected appearance of the bromide counter-ion in some of the salts we encountered (C16H21NO3·HBr), one of which is presented here [systematic name: 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide, C16H22NO3+·Br−]. Complexation of MDPV with a forensic crystallizing reagent, HAuCl4, yields the tetrachloridoaurate salt of this drug, (C16H22NO3)[AuCl4]. The heavy-metal complexing agent HAuCl4 has been used for over a century to identify common quarternary nitrogen-containing drugs via microscopic identification. Another street drug, called ethylone (3,4-methylenedioxyethylcathinone), is regularly sold and abused as its hydrochloride salt (C12H15NO3·HCl), and its structure is herein described (systematic name: N-{1-[(benzo[ d][1,3]dioxol-5-yl)carbonyl]ethyl}ethanaminium chloride, C12H16NO3+·Cl−). Marketed and sold as a `bath salt', `plant feeder', or `cleaning product', this drug is nothing more than a slight chemical modification of the banned drug methylone (3,4-methylenedioxymethcathinone). As with previously popular synthetic cathinones, the abuse of ethylone has seen a recent increase due to regulatory efforts on previous generations of cathinones that are now banned. [ABSTRACT FROM AUTHOR]

We report on a case of repeated MDPV consumptions that resulted in severe psychosis and agitation prompting the concomitant abuse of benzodiazepines. A 27-year-old man was found irresponsive in his apartment and was brought to the emergency department (ED) of a local hospital. When in ED, he rapidly recovered and self-reported to have recently injected some doses of MDPV that he had bought in the Internet. He left the hospital without medical cares. 15 days after, he was again admitted to the same ED due to severe agitation, delirium and hallucinations, and reported the use of MDPV and pharmaceutical drugs during the preceding week. He was sedated with diazepam and chlorpromazine. Urine samples collected in both occasions were sent for testing using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and liquid chromatography-high resolution multiple mass spectrometry (LC-HRMS/MS) on an Orbitrap. The LC-HRMS analysis revealed the presence of MDPV and its phase I and phase II metabolites (demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenylmethyl- oxo-MDPV, demethylenyl-hydroxy-alkyl-MDPV, demethylenyl-methyl-hydroxy alkyl-MDPV, demethylenyl-oxo-MDPV and their corresponding glucuronides), alprazolam and alprazolam metabolite at the first ED admission; at the time of the second ED access, the same MDPV metabolites, alprazolam, temazepam, and chlordiazepoxide were detected together with diazepam and metabolites. LC-HRMS/MS was use to determine the following concentrations, respectively on his first and second admission: MDPV 55 ng/mL, alprazolam 114 ng/mL, α-hydroxyalprazolam 104 ng/mL; MDPV 35 ng/mL, alprazolam 10.4 ng/mL, α-hydroxyalprazolam 13 ng/mL; chlordiazepoxide 13 ng/mL, temazepam 170 ng/mL, diazepam 1.3 ng/mL, nordiazepam 61.5, oxazepam 115 ng/mL. The toxicological findings corroborated the referred concomitant use of multiple pharmaceutical drugs and benzodiazepines. Confirmation of previous hypothesis on human metabolism of MDPV could be inferred by the analysis of urine. [ABSTRACT FROM AUTHOR]

Synthetic drugs, often marketed as ''legal highs,'' are entering the drug market at an accelerated pace. Analysis of these ''designer drugs'' and the determination of their composition are necessary in order to aid law enforcement and also to understand what potential users may be subjected to. Ten synthetic cathinones were identified in 14 separate street samples analyzed utilizing a variety of techniques, including gas chromatography with mass spectrometric detection (GC-MS) and flame ionization (GCFID). Additionally, preparatory high performance liquid chromatography (HPLC) for the fractionation of multi-component samples and the use of direct infusion tandem mass spectrometry (MS/MS) was necessary to identify compounds which were not available as reference materials. These cathinones include 3,4-methylenedioxy pyrovalerone (MDPV), 3,4-methylenedioxy-α-pyrrolidinobutiophenone (MDPBP), 4-fluoromethcathinone (4-FMC), butylone, mephedrone, naphyrone, 4-methylethcathinone (4-MEC), ethcathinone, α-pyrrolidinopentiophenone (α-PVP), and 3-methyl-α-pyrrolidinopropiophenone (3-MPPP). Concentrations of the active compounds varied between samples. For example, MDPV was determined to be the most common cathinone. It was found in five of the 14 samples and ranged from 11% to 73% between samples. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter-mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4- methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter. Findings: Bupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV >methylphenidate > bupropion). Conclusions: Bupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV > methylphenidate > bupropion). [ABSTRACT FROM AUTHOR]

In the past decade there has been a significant increase in the popularity of synthetic cathinones in the illegal drug market. They have been easily available from Interact-based vendors as well as at "head shops" and "smart shops". The recent prominence of synthetic cathinones can be attributed to their stimulatory properties similar to those of amphetamines. This paper provides a review on the current popular cathinone derivatives, their history and prevalence in the illegal drug market, legislation of these drugs in various countries, pharmacology, toxicology, and metabolism studies, analysis of toxicology samples (blood, urine, and hair) and criminalistic samples (seized, purchased via the Internet, and synthesized). From the reviewed literature, it is concluded that the products sold as "legal highs" do not only contain cathinone but also cathinone derivatives, and adulterants such as caffeine, lidocaine, and inorganic materials. Full toxicity data is currently unavailable for this drug class and hence more research is required with regard to their analysis and metabolism. Moreover, clandestine chemists are constantly synthesizing new derivatives and hence forensic chemists often need to synthesize and characterize these drugs to confirm the identity of the seized samples. This is expensive as well as time-consuming. Therefore, there is a need for national and international collaboration among forensic chemists to overcome this difficulty. [ABSTRACT FROM AUTHOR]

Abuse of psychogenic substances sold as “bath salts” and “plant food” has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active β-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported “bath salts” exposure in the USA. This study describes the clinical effects associated with “bath salt” and “plant food” exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to “bath salt” and “plant food” products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding “bath salt” or “plant food” products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation ( n = 40). Serious complications associated with reported exposure to “bath salt” and “plant food” products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful. [ABSTRACT FROM AUTHOR]

Introduction: The use of designer drugs commonly marketed as bath salts or plant food has risen dramatically in recent years. Several different synthetic cathinones have been indentified in these products, including mephedrone, 3,4-methylenedioxypyrovalerone (MDPV), and 4-fluoromethcathinone (flephedrone). We report a case of bath salt intoxication with quantitative MDPV and flephedrone levels in a patient's serum and urine, and from the bath salt product. Case Report: A 23-year-old male with a prior psychiatric history arrived via EMS for bizarre behavior, suicidality, and hallucinations after reportedly insufflating a bath salt. He was found to have MDPV levels of 186 and 136 ng/mL in his serum and urine, respectively, and flephedrone levels of 346 and 257 ng/mL in the serum and urine, respectively. The white powder in question was found to contain 143 μg MDPV and 142 μg flephedrone per milligram powder. His psychosis and agitation resolved with lorazepam, droperidol, and observation in the emergency department. Discussion: Agitation, psychosis, movement disorders, tachycardia, and hypertension have all been attributed to the use of MDPV; there are no prior reports detailing clinical experience with flephedrone. Considering that our patient's serum flephedrone levels were twofold higher than his MDPV level, it is likely flephedrone contributed to his clinical toxicity. This case suggests the possibility that fluorinated cathinones, such as flephedrone, may have altered metabolism and/or elimination which may affect their course of clinical toxicity. This case highlights the evolving composition of synthetic cathinones found in bath salt products. [ABSTRACT FROM AUTHOR]

Synthetic cathinones have recently emerged and grown to be popular drugs of abuse. Their dramatic increase has resulted in part from sensationalized media attention as well as widespread availability on the Internet. They are often considered 'legal highs' and sold as 'bath salts' or 'plant food' and labeled 'not for human consumption' to circumvent drug abuse legislation. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are derivatives of this compound. Those that are being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. Synthetic cathinones are phenylalkylamines derivatives, and are often termed 'bk-amphetamines' for the beta-ketone moiety. They may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects. Desired effects reported by users of synthetic cathinones include increased energy, empathy, openness, and increased libido. Cardiac, psychiatric, and neurological signs and symptoms are the most common adverse effects reported in synthetic cathinone users who require medical care. Deaths associated with use of these compounds have been reported. Exposure to and use of synthetic cathinones are becoming increasingly popular despite a lack of scientific research and understanding of the potential harms of these substances. The clinical similarities to amphetamines and MDMA specifically are predictable based on the chemical structure of this class of agents. More work is necessary to understand the mechanisms of action, toxicokinetics, toxicodynamics, metabolism, clinical and psychological effects as well as the potential for addiction and withdrawal of these agents. [ABSTRACT FROM AUTHOR]

Introduction: 3,4-Methylenedioxypyrovalerone (MDPV) is a designer stimulant drug that has gained popularity in the USA. Although adverse effects of MDPV have been described, to our knowledge, this is the first reported death. Case Report: We report the case of a 40-year-old male who injected and snorted 'bath salts' containing MDPV and subsequently became agitated, aggressive, and experienced a cardiac arrest. He was resuscitated after his initial arrest; however, he developed hyperthermia, rhabdomyolysis, coagulopathy, acidosis, anoxic brain injury, and subsequently died. Discussion: This is the first case in the medical literature to report death due to isolated confirmed MDPV intoxication. The manner of death is also consistent with excited delirium syndrome. [ABSTRACT FROM AUTHOR]

Background: The VP3 protein of goose parvovirus (GPV) or Muscovy duck parvovirus (MDPV), a major structural protein, can induce neutralizing antibodies in geese and ducks, but monoclonal antibodies (MAbs) against VP3 protein has never been characterized. Results: Three hybridoma cell lines secreting anti-GPV VP3 MAbs were obtained and designated 4A8, 4E2, and 2D5. Immunoglobulin subclass tests differentiated them as IgG2b (4A8 and 4E2) and IgG2a (2D5). Dot blotting assays showed that three MAbs reacted with His-VP3 protein in a conformation-independent manner. A competitive binding assay indicated that the MAbs delineated two epitopes, A and B of VP3. Immunofluorescence assay showed that MAbs 4A8, 4E2, and 2D5 could specifically bind to goose embryo fibroblast cells (GEF) or duck fibroblast cells (DEF) infected with GPV and MDPV. Dot blotting also showed that the MAbs recognized both nature GPV and MDPV antigen. Western blotting confirmed that the MAbs recognized VP3 proteins derived from purified GPV and MDPV particles. The MAbs 4A8 and 2D5 had universal reactivity to heterologous GPV and MDPV tested in an antigen-capture enzyme-linked immunosorbent assay. Conclusions: Preparation and characterization of these the MAbs suggests that they may be useful for the development of a MAb-capture ELISA for rapid detection of both GPV and MDPV. Virus isolation and PCR are reliable for detecting GPV and MDPV infection, but these procedures are laborious, time-consuming, and requiring instruments. These diagnosis problems highlight the ongoing demand for rapid, reproducible, and automatic methods for the sensitive detection of both GPV and MDPV infection. [ABSTRACT FROM AUTHOR]

Abstract: Starting in 2008 a new designer drug, 3,4-methylenedioxypyrovalerone (MDPV) appeared among users of illegal drugs in Finland. Since then there have been several seizures of MDPV by police and customs and it has been connected to many crimes of different types. In this study the incidence and impact of the use of MDPV in drivers suspected of being under the influence of drugs (DUID) in Finland was assessed. Since autumn 2009, blood samples from drivers suspected of DUID in Finland have been analysed for the presence of MDPV. A new LC–MS/MS method for the determination of MDPV in serum was established. In order to assess the impact of MDPV on driving performance, drug and alcohol findings of positive MDPV cases were compared with data from the clinical examination carried out while the suspect was under arrest. In a period of one year there were 259 positive MDPV cases from apprehended drivers (5.7% of all confirmed DUID cases). In 80% of the cases in which MDPV was found, amphetamine was also present. Benzodiazepines were also frequently found together with MDPV, which was to be expected since in Finland, in our experience, stimulants are very often used together with benzodiazepines. In most cases it remained unclear whether the observed psycho-physical achievement deficiency was induced by MDPV because the concentrations of other drugs, especially other stimulants, were often high. However, in some subjects, MDPV, or MDPV in combination with other substances was the most probable cause of the impairment. The concentrations of MDPV varied from 0.016mg/L to over 8.000mg/L. Little is known about the pharmacology of MDPV. However, based on our findings it is clear that MDPV has a serious impact on traffic safety in Finland. [Copyright &y& Elsevier]

Background: In the recent years, a new group of designer drugs, under the brand name of bath salts has emerged as a new trend. They are mainly b-ketone amphetamine analogs and are derivatives of cathinone, a monoamine alkaloid. They are abused for psychostimulant effects. Their primary ingredient 3,4-methylenedioxypyrovalerone (MDPV), has alerted authorities worldwide due to its severe physiological and behavioral toxicities. Description of Case:We present the case of a 47-year-old man with coma, seizures, multi-organ failure and ischemic colitis after intoxication with bath salts containing MDPV. After supportive care, he had a successful outcome. To our knowledge, this report is the first to describe ischemic colitis after MDPV intoxication. Clinicians need to be especially alert since MDPV is not detected by routine screens, and its overdose can be life-threatening. Conclusion: Ischemic colitis should be recognized as a potential complication of bath salts ingestion in order to prevent unnecessary interventions, such as diagnostic laparotomy, which could worsen patient's condition. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed. [ABSTRACT FROM AUTHOR]

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity. [ABSTRACT FROM AUTHOR]