Understanding methiopropamine, a new psychoactive substance: an in-depth review on its chemistry, pharmacology and implications to human health.

Methiopropamine or 1-(thiophen-2-yl)-2-methylaminopropane (MPA) is a thiophene ring-based structural analogue of methamphetamine, first synthesized in 1942 but become popular when it started to be available for purchase on websites selling 'legal highs' since 2010. While it is legally controlled in many countries, it remains readily accessible and frequently encountered in recreational settings. The growing prevalence of MPA use results in new therapeutic challenges. Relatively few studies have focused on its pharmacodynamics and pharmacokinetics, making it important to better understand its potential risks and harmful effects in humans in terms of its toxicity. This review provides a comprehensive profiling of MPA toxicological properties, including its chemical properties, analytical methods, prevalence, patterns of use, and legal status. Additionally, it discusses the drug's effects on the central nervous system, its potential for addiction, and its adverse physical and mental health effects. Improving the understanding of safety aspects of MPA and how it imposes health threats for public health will guide the development of therapeutic approach of its intoxication and guide the authorities in deciding its legal status.

Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.

The 3,4-methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.

Neurotransmitter and psychostimulant recognition by the dopamine transporter.

Na(+)/Cl(-)-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

An updated review on synthetic cathinones.

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a ß-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.

[ß-Glu2]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain.

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.

Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents.

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (Emax 12.5 mg/kg; i.p.) compared to methamphetamine (Emax 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC50 = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC50 > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.

Modulatory Effects of Caffeine and Pentoxifylline on Aromatic Antibiotics: A Role for Hetero-Complex Formation.

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M-1 and enthalpy change values up to -4 kJ·M-1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.

Percutaneous absorption between frog species: Variability in skin may influence delivery of therapeutics.

Frogs have permeable skin, so transdermal delivery provides a practical alternative to traditional dosing routes. However, little is known about how frog skin permeability differs interspecifically, and there are different reported clinical outcomes following topical application of the same chemical in different frog species. This study collated in vitro absorption kinetic data previously reported for two frog species: the green tree frog (Litoria caerulea) and the cane toad (Rhinella marina), and used linear mixed-effects modelling to produce a model of absorption. Histology of skin samples from each species was performed to observe morphological differences that may affect absorption. Absorption kinetics differed significantly between species, with the logP of the applied chemical a better predictor of permeability than molecular weight. Application site also influenced permeability, with dorsal permeability consistently higher in cane toads. Ventral permeability was more consistent between species. Skin thickness differed between species and skin regions, and this may explain the differences in absorption kinetics. Guidelines for selecting chemicals and dosing site when treating frogs are presented. The permeability differences identified may explain the poor reproducibility reported in the treatment of disease across frog species, and reinforces the importance of considering interspecies differences when designing therapeutic treatments for frogs.

Chromatographic separation of R-(-)/S-(+)-enantiomers of amphetamine and methamphetamine: differentiation between single methamphetamine consumption and co-consumption with amphetamine using enantioselective quantitative LC-MS/MS analysis.

The differentiation between single methamphetamine consumption and co-consumption with amphetamine is difficult, however possible by enantioselective analysis due to different preferred synthesis pathways of both substances. We quantified (R)-(-) and (S)-(+)-enantiomers of methamphetamine and amphetamine by a fast liquid chromatographic tandem-mass spectrometric method using a Lux® 3-µm AMP 150 × 3.0 mm analytical column after simple protein precipitation with methanol. Method validation for quantitative detection showed limits of quantification < 5 ng/mL, linearity in a range between 5 and 300 ng/mL and bias and imprecision data < 15%. Overall, 134 plasma samples of police cases from the German regions of Franconia and Northrhine-Westphalia were analyzed for the enantiomers of methamphetamine and amphetamine. In 28 cases, the intake of racemic illicit amphetamine could be demonstrated; (R)-(-) / (S)-(+)-amphetamine concentration ratios in these cases were between 1.38 and 4.50 with most of the ratios being < 2.0. These ratios were compared to a subgroup of 25 consumers with a co-consumption of (S)-(+)-methamphetamine and racemic amphetamine detected by the qualitative proof of (R)-(-)-amphetamine but also by (R)-(-) / (S)-(+)-amphetamine concentration ratios (< 1 in 11 of 25 cases). Within our collective of 106 plasma samples after methamphetamine use, 25 samples showed co-consumption with amphetamine which shows that co-consumption of both stimulants is not a rare scenario. Furthermore, we could show that if non-stereoselective methods are used and the concentration ratio of total methamphetamine/total amphetamine is determined, a reliable estimation of co-consumption is not possible.

A new insight into the oxidative mechanism of caffeine and related methylxanthines in aprotic medium: May caffeine be really considered as an antioxidant?

BACKGROUND: Antioxidant properties have been recently suggested for caffeine that seems showing protective effects against damages caused by oxidative stress. In particular, a HO scavenging activity has been ascribed to caffeine. Even if the oxidation of caffeine has been widely studied, the antioxidant mechanism is still far to be understood. METHODS: The electrochemical behavior of caffeine, theobromine and theophylline was studied in aprotic medium by cyclic voltammetry and electrolysis in UV-vis cell; a computational analysis of the molecular structures based on the Density Functional Theory was performed; the reactivity of all substrates towards lead dioxide, superoxide and galvinoxyl radical was followed by UV-vis spectrophotometry. RESULTS: Results supported the mono-electronic oxidation of the C4C5 bond for all substrates at high oxidation potentials, the electron-transfer process leading to a radical cation or a neutral radical according to the starting methylxanthine N7-substituted (caffeine and theobromine) or N7-unsubstituted (theophylline), respectively. A different following chemical fate might be predicted for the radical cation or the neutral radical. No interaction was evidenced towards the tested reactive oxygen species. CONCLUSIONS: No reactivity via H-atom transfer was evidenced for all studied compounds, suggesting that an antiradical activity should be excluded. Some reactivity only with strong oxidants could be predicted via electron-transfer. The acclaimed HO scavenging activity should be interpreted in these terms. The study suggested that CAF might be hardly considered an antioxidant. GENERAL SIGNIFICANCE: Beyond the experimental methods used, the discussion of the present results might provide food for thought to the wide audience working on antioxidants.

Inhibitory effects of some drugs on carbonic anhydrase enzyme purified from Kangal Akkaraman sheep in Sivas, Turkey.

In this study, carbonic anhydrase (CA) enzyme was purified and characterized from blood samples of Kangal Akkaraman sheep and inhibitory properties on certain antibiotics were examined. CA purification was composed of preparation of the hemolysate and conducting the Sepharose-4B-tyrosine-sulfanilamide affinity gel chromatography in having specific activity of 11626 EU mg-1 , yield of 14.40%, and 242.76-fold purification. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed to assess the enzyme purity and a single band was observed. Some antibiotics were exhibited in vitro inhibition on the CA activity. IC50 values of these inhibitors were calculated by plotting activity percentage. IC50 values of certain drugs (dexamethasone; caffeine; metamizole sodium; tetramisol; ceftiofur HCl; ivermectin; tavilin 50; penokain G; neosym; and sulfamezathine) were found as 0.38, 8.24, 285.53, 114.77, 5.33, 2.76, 27.58, 213.50, 208.28, and 36.60 µM, respectively. Ki values of different drugs on Kangal Akkaraman sheep blood CA activity were found in the range of 0.21 ± 0.038-266.64 ± 37.11 µM.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone.

Mephedrone (MEPH) is a ß-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a ß-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the ß-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.

Impact of common clandestine structural modifications on synthetic cathinone "bath salt" pharmacokinetics.

Since 2009, the synthetic cathinones ("bath salts") have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3). Male Sprague-Dawley rats were treated with a 20mg/kg subcutaneous dose of the individual synthetic cathinone. Blood samples were obtained at specific times from a jugular vein cannula over an 8hour period. Over a separate three-hour period, CNS samples were obtained using a microdialysis cannula surgically implanted into the lateral ventricle. In the plasma, pentylone, with the longest α-alkyl chain, displayed the highest Cmax and AUC0-∞, and the longest t1/2. Decreasing the α-alkyl chain length as in butylone and methylone significantly decreased the Cmax, AUC0-∞, and t1/2. The plasma pharmacokinetic values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher Cmax and AUC0-∞ values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential pharmacokinetic properties in the CNS as compared to the plasma.

Intended and unintended use of cathinone mixtures.

INTRODUCTION: Cathinones are one of the most popular categories of new psychoactive substances (NPS) consumed. Cathinones have different pharmacological activities and receptor selectivity for monoamine transporters based on their chemical structures. They are incorporated into NPS mixtures and used with other NPS or 'traditional' drugs. Cathinone use represents significant health risks to individuals and is a public health burden. METHODS: Evidence of poly-NPS use with cathinones, seizure information, and literature analyses results on NPS mixtures was systematically gathered from online database sources, including Google Scholar, Scopus, Bluelight, and Drugs-Forum. RESULTS AND DISCUSSION: Results highlight the prevalence of NPS with low purity, incorporation of cathinones into NPS mixtures since 2008, and multiple members of the cathinone family being present in individual UK-seized samples. Cathinones were identified as adulterants in NPS marketed as being pure NPS, drugs of abuse, branded products, herbal blends, and products labelled "not for human consumption." Toxicity resulting from cathinone mixtures is unpredictable because key attributes remain largely unknown. Symptoms of intoxication include neuro-psychological, psychiatric, and metabolic symptoms. Proposed treatment includes holistic approaches involving psychosocial, psychiatric and pharmacological interventions. CONCLUSION: Raising awareness of NPS, education, and training of health care professionals are paramount in reducing harms related to cathinone use.

[Identification of Methamphetamine Abuse and Selegiline Use： Chiral Analysis of Methamphetamine and Amphetamine in Urine].

OBJECTIVES: To study the content variation of selegiline and its metabolites in urine, and based on actual cases, to explore the feasibility for the identification of methamphetamine abuse and selegiline use by chiral analysis. METHODS: The urine samples were tested by chiral separation and LC-MS/MS method using CHIROBIOTIC™ V2 chiral liquid chromatography column. The chiral analysis of methamphetamine and amphetamine were performed on the urine samples from volunteers of selegiline use and drug addicts whom suspected taking selegiline. RESULTS: After 5 mg oral administration, the positive test time of selegiline in urine was less than 7 h. The mass concentrations of R（-）-methamphetamine and R（-）-amphetamine in urine peaked at 7 h which were 0.86 µg/mL and 0.18 µg/mL and couldn't be detected after 80 h and 168 h, respectively. The sources of methamphetamine and amphetamine in the urine from the drug addicts whom suspected taking selegiline were analysed successfully by present method. CONCLUSIONS: The chiral analysis of methamphetamine and amphetamine, and the determination of selegiline's metabolites can be used to distinguish methamphetamine abuse from selegiline use.

New Psychoactive Substances: Chemistry, Pharmacology, Metabolism, and Detectability of Amphetamine Derivatives With Modified Ring Systems.

In recent years, new amphetamine derivatives with modified ring systems were sold and consumed as new drugs of abuse. They belong together with other new drugs of abuse classes to the so-called new psychoactive substances (NPS). The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics are shortly discussed of camfetamine, 3 methylphenyl-amphetamines (2-MA, 3-MA, and 4-MA), 2-methiopropamine (2-MPA), and 5-(2-aminopropyl)benzofuran (5-APB), 6-(2-aminopropyl)benzofuran (6-APB, so-called "benzofury") and their N-methyl derivatives 5-MAPB and 6-MAPB. Only a rough assessment of the pharmacology and toxicology NPS can be performed in most cases using published data of analogs, trip reports, and described clinical cases. Accordingly, they all act more or less as central nervous stimulants mainly by increasing the concentration of the neurotransmitters noradrenaline, dopamine, and serotonin (5-HT) by inducing their release and reuptake inhibition. Thus, the acute toxicity is associated with the sympathomimetic effects, such as mydriasis, hyperthermia, hypertension, tachycardia, insomnia, and anxiety. With the exception of 5- and 6-APB, these NPS were extensively metabolized by N-demethylation and/or aromatic hydroxylation catalyzed by various cytochrome P450 isoenzymes followed by partial glucuronidation and/or sulfation. For urinalysis, the unchanged drugs and/or the nor-metabolites are the main targets.

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives.

Synthetic cathinones, often sold as "bath salts," are a popular class of recreational drugs used as quasi-legal alternatives to cocaine, methamphetamine, and methylenedioxymethamphetamine. The increased prevalence and health consequences of synthetic cathinone use has prompted regulatory agencies to control a number of these compounds; however, a broad class of analogous compounds known as the second-generation cathinones has been brought to the market to take the place of the banned synthetic cathinone derivatives. The current study aims to characterize the behavioral pharmacology of three pyrrolidinylated second-generation cathinones: 4-methyl-α-pyrrolidinopropiophenone (4'-MePPP), α-pyrrolidinopropiobutiophenone (α-PBP), and α-pyrrolidinopentiophenone (α-PVP). Locomotor activity was tested in mice over an 8-hour period. The discriminative stimulus effects of these compounds were tested in rats trained to discriminate either cocaine or methamphetamine. The rewarding effects of these drugs were assessed in mice using conditioned place preference. Both α-PBP and α-PVP produced long-lasting increases in locomotor activity across a wide range of doses, whereas 4'-MePPP produced locomotor stimulation only at 30 mg/kg. Both α-PBP and α-PVP fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine, whereas 4'-MePPP substituted fully for the discriminative stimulus effects of methamphetamine only. Both α-PBP and α-PVP produced conditioned place preference in an inverted U-shaped dose effect, whereas 4'-MePPP did not produce conditioned place preference. These findings suggest that α-PBP and α-PVP are likely to be recreationally used and have potential for addiction and abuse, but 4'-MePPP may not.

Caffeine impairs gastrointestinal function in newborn rats.

BACKGROUND: Feeding intolerance is commonly documented in premature infants. Caffeine is routinely utilized for apnea of prematurity treatment and known to reduce the lower esophageal sphincter (LES) muscle tone, but the caffeine effect on the newborn gastrointestinal function is unknown. We hypothesized that caffeine impairs esophageal and gastrointestinal motor function. As such, we investigated the drug effect on the tissue's mechanical properties and the newborn rat's in vivo gastric emptying rate. METHODS: The effects of caffeine on LES, gastric fundal and antrum, as well as ileal and colonic muscle force potential and relaxation response, were measured in newborn and adult rats. The caffeine-induced (10 mg/kg i.p.) newborn gastric emptying rate changes were evaluated following 3 h of fasting. RESULTS: Caffeine relaxed the precontracted LES and fundal muscle (P < 0.01), reduced the gastric and intestinal muscle contraction (P < 0.01), and delayed the pups' gastric emptying time (P < 0.01). The caffeine-induced muscle relaxant effect was independent of age and mediated via ryanodine receptors. CONCLUSION: Caffeine administration to newborn rats at a dose comparable to the one therapeutically used for preterm neonates impairs LES and gastrointestinal motor function. Further clinical investigation on the possible contribution of caffeine to neonatal feeding intolerance is warranted.

Screening determination of four amphetamine-type drugs in street-grade illegal tablets and urine samples by portable capillary electrophoresis with contactless conductivity detection.

A simple and inexpensive method for the identification of four substituted amphetamines, namely, 3,4-methylenedioxy methamphetamine (MDMA), methamphetamine (MA), 3,4-methylenedioxy amphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDEA) was developed using an in-house constructed semi-automated portable capillary electrophoresis instrument (CE) with capacitively coupled contactless conductivity detection (C(4)D). Arginine 10mM adjusted to pH4.5 with acetic acid was found to be the optimal background electrolyte for the CE-C(4)D determination of these compounds. The best detection limits achieved with and without a sample preconcentration process were 10ppb and 500ppb, respectively. Substituted amphetamines were found in different seized illicit club drug tablets and urine samples collected from different suspected users. Good agreement between results from CE-C(4)D and those with the confirmation method (GC-MS) was achieved, with correlation coefficients for the two pairs of data of more than 0.99.

Effects of α-pyrrolidinopentiophenone and 4-methyl-N-ethylcathinone, two synthetic cathinones commonly found in second-generation "bath salts," on intracranial self-stimulation thresholds in rats.

BACKGROUND: Use of synthetic cathinones, which are designer stimulants found in "bath salts," has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements. METHODS: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α-pyrrolidinopentiophenone (0.1-5 mg/kg) and 4-methyl-N-ethcathinone (1-100 mg/kg) on brain reward function. Methamphetamine (0.1-3 mg/kg) was also tested for comparison purposes. RESULTS: Results revealed both α-pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. α-Pyrrolidinopentiophenone (1 mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1 mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N-ethcathinone were observed at 30 mg/kg (~15%) and were comparable with those observed with methamphetamine and α-pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log-transformed data revealed the rank order potency of these drugs as methamphetamine ≈ α-pyrrolidinopentiophenone>4-methyl-N-ethcathinone. CONCLUSIONS: These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported.