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Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner., Methods: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)., Results and Discussion: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen., Conclusions: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used., (© 2020 John Wiley & Sons, Ltd.)

Background: The prevalence of drug use during pregnancy continues to increase despite the associated serious adverse obstetrical outcomes, including increased risk of miscarriage, fetal growth restriction, brain development impairment, neonatal abstinence syndrome, preterm delivery, and stillbirths. Monitoring drug use during pregnancy is crucial to limit prenatal exposure and provide suitable obstetrical health care. The authors reviewed published literature reporting the concentrations of common drugs of abuse and new psychoactive substances (NPS), such as synthetic cathinones and synthetic opioids, NPS, and their metabolites using unconventional matrices to identify drug use during pregnancy and improve data interpretation., Methods: A literature search was performed from 2010 to July 2019 using PubMed, Scopus, Web of Science scientific databases, and reports from international institutions to review recently published articles on heroin, cocaine, amphetamine, methamphetamine, synthetic cathinone, and synthetic opioid monitoring during pregnancy., Results: Meconium has been tested for decades to document prenatal exposure to drugs, but data regarding drug concentrations in amniotic fluid, the placenta, the umbilical cord, and neonatal hair are still lacking. Data on prenatal exposure to NPS are limited., Conclusions: Maternal hair testing is the most sensitive alternative matrix for identifying drug use during pregnancy, while drug concentrations in the meconium, placenta, and umbilical cord offer the identification of prenatal drug exposure at birth. Adverse developmental outcomes for the infant make it critical to promptly identify maternal drug use to limit fetal exposure or, if determined at birth, to provide resources to the exposed child and family. Alternative matrices offer choices for monitoring and challenge laboratories to deliver highly sensitive and specific analytical methods for detection.

Background: The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed., Methods: The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals., Results: Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication., Conclusions: A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.

This work aimed to continue our effort in establishing the feasibility of 3-fluoroamphetamine (also known as PAL-353) to be a transdermal drug candidate by studying the delivery of the base form through the human cadaver skin in lieu of the previously investigated salt form, and for the first time using an EPIDERM™-reconstructed human epidermal model to predict the skin irritation potential of PAL-353, in support of development for a matrix-type transdermal delivery system. Passive and enhanced (with chemical permeation enhancers) transdermal delivery were investigated via in vitro permeation studies that were performed on Franz diffusion cells with dermatomed human cadaver skin. After 24 h, PAL-353 free base revealed high passive permeation of 417.49 ± 30.12, 1577.68 ± 165.41, and 4295.16 ± 264.36 μg/cm 2 , with applied formulation concentrations of 5.5 (F1), 20 (F2), and 40 (F3) mg/mL, respectively. Oleyl alcohol produced an approximately threefold steady-state flux enhancement at 5% or 10% w/w but may not be needed as the free base alone provided therapeutically relevant permeation. Further, it was predicted that therapeutically relevant delivery would be unlikely to cause skin irritation using the EPIDERM™-reconstructed human epidermal model. In conclusion, the present study further supported the development of PAL-353 transdermal delivery systems.

Each year, synthetic drugs are occurring in high numbers in the illicit drug market. But data on their pharmacology and toxicology are scarcely available. Therefore, a pilot study was performed to evaluate excretion of 4-fluoroamphetamine (4FA) in humans and identify metabolites in urine. Twelve subjects ingested 100 mg and five 150 mg 4-FA in a bitter lemon drink. Urine samples were scheduled at baseline and 4 times during the following 12 h and analyzed by liquid chromatography-mass spectrometry (LC-MSMS). Concentrations of 4-FA were in the range of 0.7-38 mg/l which is in accordance with the data in previously reported cases. A marked decrease of creatinine excretion in the first two samples was noted. The creatinine normalized concentrations show a maximum 4 h after ingestion in accordance with serum pharmacokinetics. Three products of two metabolic pathways were identified in very low concentrations, two diastereomers of 4-fluorophenylpropanolamine and one ring hydroxylated 4-FA that was conjugated to a large extent. The concentration-time courses paralleled those of 4-FA. The study results show the range of 4-FA concentrations to be expected in urine after oral ingestion of typical dosages and show two pathways of 4-FA metabolism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C 0 (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 h. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm 2 ). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~ 70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.

Introduction: Each year, synthetic drugs occur in high numbers on the illicit drug market. But data on their pharmacology and toxicology are scarce. Therefore, a controlled study was performed to evaluate pharmacokinetic parameters of 4-fluoroamphetamine (4-FA) in humans and to compare it with effects., Methods: Twelve subjects ingested 100 mg and five subjects also received 150 mg 4-FA in a bitter lemon drink. Blood and oral fluid samples were taken during the following 12 hours and analyzed for 4-FA and traces of amphetamine as impurity by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: For 12 hours after ingestion, the concentration-time course of 4-FA was similar to that of amphetamine with maximal concentrations appearing in serum after about 2 hours (in median 195 ng/mL after the 100 mg dose, range 155-316 ng/mL). The elimination half-life was approximately 8-9 hours and shorter than that of amphetamine but it exhibited a marked variation (5.5-16.8 hours). In oral fluid, 4-FA could also be detected for 12 hours and concentrations were higher than in serum. During the first 3 hours after ingestion concentrations were higher, most probably due to oral contamination. Serum concentrations in forensic cases were in the range of those observed in the present study suggesting dosages in recreational use in the range of those tested here., Conclusions: The pharmacokinetic properties of 4-FA are similar to that of amphetamine including a marked variation in elimination. However, recreational dosages may already exhibit prominent adverse effects and may even have life-threatening consequences., (© 2019 John Wiley & Sons, Ltd.)

Background: Chiral analysis is a crucial way to differentiate selegiline (SG) intake from drug abuse. Oral fluid (OF) has been successfully used as an alternative matrix for blood testing in several pharmacokinetic studies., Objective: The aim of this study is to describe the pharmacokinetics of SG and its main metabolites in OF after a single oral administration of SG which is meaningful for results interpretation in forensic analysis., Methods: Ten milligrams of SG were orally administered to 8 volunteers, and OF samples were collected for up to 96 hours by having participants spit into polypropylene tubes without stimulation. These samples were submitted to liquid-liquid extraction before analysis by liquid chromatography-tandem mass spectrometry operating in positive ion multiple-reaction monitoring mode., Results and Conclusions: After oral administration, each analyte could be detected in OF specimens from all volunteers with an initial detection time of 0.50 hours. The C max values of SG, R-MA, R-AM and DM-SG were 50.93-992.67 ng/mL, 29.78-653.64 ng/mL, 8.22-150.15 ng/mL, and 4.34-16.25 ng/mL, respectively, at 0.5 hours, 1-11 hours, 1.5-11 hours, and 0.5-6 hours post dose. The times when the compounds were last determined in OF were 5-24 hours for SG, 52-96 hours for R-MA, 31-96 hours for R-AM, and 13-31 hours for DM-SG after oral administration. There is a period of time in OF in which only MA and AM are present without SG and DM-SG after a single dose of SG. The pharmacokinetic data could provide supplementary interpretation for OF tests in forensic science and drug treatment programs., (© 2019 John Wiley & Sons, Ltd.)

The widespread diffusion of new psychoactive substances, requires a continuous update and development of new methods able to identify and quantify these new molecules in biological matrices. In this study an analytical method for the determination of two new benzodifuranyl derivatives, 1-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)propan-2-amine and 2-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)ethanamine, in rat plasma was developed. A solid phase extraction using C18 cartridges was carried out obtaining good recoveries with low matrix effect. Quantification was performed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Separation was carried out on a C18 reverse phase column with water/methanol containing 0.1% of formic acid as mobile phase. These conditions allowed to achieve adequate separation, resolution and signal-to-noise ratio for analytes and internal standard. Calibration curves were linear over the concentration range from 10 to 400 ng/ml with correlation coefficients that exceeded 0.995. Obtained precision, accuracy and recovery showed good reproducibility and selectivity. Finally, the validation method was successfully applied to an in vivo study in order to evaluate the pharmacokinetic profile of these new amphetamines., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rationale: The synthetic cathinones are a class of designer drugs of abuse that share a common core scaffold. The pharmacokinetic profiles of the synthetic cathinones vary based on the substitutions to the core scaffold., Objectives: To provide a summary of the literature regarding the pharmacokinetic characteristics of the synthetic cathinones, with a focus on the impact of the structural modifications to the pharmacokinetics., Results: In many, but not all, instances the pharmacokinetic characteristics of the synthetic cathinones can be reasonably predicted based on the substitutions to the core scaffold. Mephedrone and methylone are chemically alike and have similar T max and t 1/2 in male rats. MDPV, a structurally distinct synthetic cathinone from mephedrone and methylone, has a lower T max and t 1/2 . Increasing the length of the alkyl chain on the α position of methylone, to produce pentylone, results in increased plasma concentrations and longer t 1/2 . Metabolism of the synthetic cathinones is reasonably predictable based on the chemical structure, and several phase I metabolites retain pharmacodynamic activity. CYP2D6 is implicated in the metabolism of all of the synthetic cathinones, and other P450s (CYP1A2, CYP2B6, and CYP2C19) are known to contribute variably to the metabolism of specific synthetic cathinones., Conclusions: Continued research will lead to a better understanding of the pharmacokinetic changes associated with structural modifications to the cathinone scaffold, and potentially in the long range, enhanced overdose and addiction therapy. Additionally, the areas of polydrug use and pharmacogenetics have been largely overlooked with regard to synthetic cathinones.

Oral fluid analysis for drugs is increasingly used in a variety of testing areas: pain management and medication monitoring, parole and probation situations, driving under the influence of drugs (DUID), therapeutic drug monitoring, and testing for drugs in the workplace. The sample collection itself is straightforward, rapid, observable, and noninvasive, requiring no special facilities (compared to urine) or medical personnel (compared to blood). The pH of saliva is slightly acidic relative to blood; therefore, drugs which are more basic tend to be present in higher concentration in oral fluid than in blood: cocaine, amphetamines, oxycodone, tramadol, buprenorphine, methadone, and fentanyl. Conversely, acidic drugs and drugs which are strongly protein bound have lower concentrations in oral fluid than in blood: examples include benzodiazepines, barbiturates, and carisoprodol. Because of the low volume of specimen available for analysis and the drug concentrations present (generally much lower than those in urine), efficient extraction methods and sensitive confirmation procedures are necessary for routine analysis of drugs in oral fluid. In this chapter, solid-phase extraction methods are described for a variety of drugs with liquid chromatography-tandem mass spectrometry detection.

Meconium, the first stool of a newborn, can be analyzed to identify prenatal exposure to drugs of abuse. Meconium accumulates in a fetus during the second and third trimesters of pregnancy providing a wide window of exposure. Identification of in utero drug exposure is essential for the diagnosis and treatment of infants for dependency/withdrawal caused from the exposure. However, testing of meconium samples is often cumbersome and time-consuming. Unlike liquid samples, meconium is a viscous, semisolid, tar-like substance that needs to be individually weighed prior to extraction. Additionally, the meconium matrix is not homogeneous and not easily mixed or extracted. A method for analyzing cocaine and metabolites as well as amphetamines in meconium utilizing ceramic homogenizers prior to salt-assisted liquid-liquid extraction and liquid chromatography tandem-mass spectrometry (LC-MS/MS) is presented.

Amphetamines and the nonamphetamine atomoxetine are commonly used in the treatment of attention-deficit disorder/attention-deficit/hyperactivity disorder in humans. Because these medications are often found in homes, dog and cat exposure to these medications is a common intoxication. Amphetamine intoxication can cause life-threatening central nervous system and cardiovascular stimulation, even when small amounts are ingested., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans; for this purpose, we used human liver microsomes (HLMs) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism by using genotyped HLMs isolated from CYP2D6 poor, population-average, and ultrarapid metabolizers. In HLMs, PMMA was metabolized mainly to 4-hydroxymethamphetamine (OH-MA), whereas low concentrations of para-methoxyamphetamine (PMA), 4-hydroxyamphetamine (OH-A), dihydroxymethamphetamine (di-OH-MA), and oxilofrine were formed. The metabolite profile in the fatal PMMA intoxications were in accordance with the HLM study, with OH-MA and PMA being the major metabolites, whereas OH-A, oxilofrine, HM-MA and HM-A were detected in low concentrations. A significant influence of CYP2D6 genetics on PMMA metabolism in HLMs was found. The catechol metabolite di-OH-MA has previously been suggested to be involved in PMMA toxicity. Our studies show that the formation of di-OH-MA from PMMA was two to seven times lower than from an equimolar dose of the less toxic drug MDMA, and do not support the hypothesis of catechol metabolites as major determinants of fatal PMMA toxicity. The present study revealed the metabolite pattern of PMMA in humans and demonstrated a great impact of CYP2D6 genetics on human PMMA metabolism., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Amphetamine (AMP), an indirectly acting psychostimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults, is among the most long-standing therapeutic agents in all of clinical psychopharmacology. This review focuses on AMP absorption, metabolism, and elimination brought to bear on comparative pharmacokinetics in its various formulations. A comprehensive search of the published literature was conducted using MEDLINE (PubMed) and Google Scholar databases through April 2017 to retrieve all pertinent in vitro and human studies for review and synthesis. Additionally, Food and Drug Administration (FDA) databases were accessed for otherwise unavailable data when possible. Initially available as racemic (dl)-AMP, this drug was later supplanted by enantiopure (d)-AMPH or enantioenriched (75:25 dl)-AMP formulations; although racemic AMP returned as an approved drug to treat ADHD in 2014. Presently, there are several immediate-release (IR) formulations available, including d-AMP, dl-AMP, and mixed amphetamine salts, which are neither racemic nor the pure d-enantiomer (i.e., a 3:1 mixture of d-AMP and l-AMP). Furthermore, new modified-release AMP formulations, including an oral suspension and an orally disintegrating tablet, are now available. A lysine-bonded prodrug form of d-AMP also serves as a treatment option. Oral AMP is rapidly absorbed, with high absolute bioavailability, followed by extensive metabolism involving multiple enzymes. Some metabolic pathways exhibit stereoselective biotransformations favoring the l-isomer substrate. Drug exposure exhibits dose-proportional pharmacokinetics. Body weight is a fundamental determinant of differences in observed AMP plasma concentrations. IR formulations typically provide a T max from 2 to 3 hours. In replicated studies, children exhibit a shorter plasma T 1/2 (∼7 hours) relative to adults (∼10 to 12 hours). There are few documented pharmacokinetic drug interactions of clinical significance beyond influences of drug-induced alteration of urinary pH. The array of AMP formulations addressed in this review offer flexibility in dosing, drug onset, and offset to assist in individualized pharmacotherapy of ADHD.

Rationale: Recent years have seen an increase in the recreational use of novel, synthetic psychoactive substances. There are little or no data on the abuse liability of many of the newer compounds., Objectives: The current study investigated the discriminative stimulus and locomotor effects of a series of synthetic analogs of cathinone: α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinohexiophenone (α-PHP), α-pyrrolidinopentiothiophenone (α-PVT), 3,4-methylenedioxybutiophenone (MDPBP), and ethylone., Methods: Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine or methamphetamine from vehicle., Results: Each of the compounds produced an inverted-U dose-effect on locomotor activity. Maximal effects were similar among the test compounds, but potencies varied with relative potencies of MDPBP > α-PPP = α-PHP > ethylone > α-PVT. Each of the test compounds substituted fully for the discriminative stimulus effects of methamphetamine. α-PPP, α-PHP, and ethylone fully substituted for cocaine. α-PVT produced a maximum of 50% cocaine-appropriate responding, and MDPBP produced an inverted-U-shaped dose-effect curve with maximum effects of 67%., Conclusions: These data provide initial evidence that these structurally similar, emerging novel psychoactive substances demonstrate potential for abuse and may be utilized for their stimulant-like effects, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of the classical psychostimulants cocaine and/or methamphetamine.

We present a case of "ecstasy" ingestion revealing 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dimethoxyamphetamine (3,4-DMA) and absence of cytochrome P450 (CYP)-2D6 MDMA metabolites., Case Report: A 19-year-old presented following a seizure. Initial vital signs were normal. Laboratories were normal with the exception of sodium 127 mEq/L and urine drugs of abuse screen positive for amphetamines. Twelve hours later, serum sodium was 114 mEq/L and a second seizure occurred. After receiving hypertonic saline (3%), the patient had improvement in mental status and admitted to taking "ecstasy" at a rave prior to her initial presentation. Liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS) of serum and urine revealed MDMA, 3,4-DMA, and the CYP-2B6 MDMA metabolites 3,4-methylendioxyamphetamine (MDA) and 4-hydroxy-3-methoxyamphetamine (HMA). The CYP2D6 metabolites of MDMA, 3,4-dihydromethamphetamine (HHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), were detected at very low levels., Conclusion: This case highlights the polypharmacy which may exist among users of psychoactive illicit substances and demonstrates that concurrent use of MDMA and 3,4-DMA may predispose patients to severe toxicity. Toxicologists and other healthcare providers should be aware of this potential toxicity.

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.

Background: Recently, the number of new psychoactive substances (NPS) appearing on the illicit drug market has shown a marked increase. Although many users perceive the risk of using NPS as medium or low, these substances can pose a serious health risk and several NPS have been implicated in drug-related deaths. In Europe, frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA) and benzofurans (5-(2-aminopropyl)benzofuran (5-APB) or 6-(2-aminopropyl)benzofuran (6-APB)). However, little is known about the health risks of these specific NPS., Methods: In this paper, existing literature on the pharmacokinetics and pharmacodynamics of 2C-B, 4-FA and benzofurans (5-APB/6-APB) was reviewed., Results: Our review showed that the clinical effects of 2C-B, 4-FA and benzofurans (5-APB/6-APB) are comparable with common illicit drugs like amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Therefore, NPS toxicity can be handled by existing treatment guidelines that are based on clinical effects instead of the specific drug involved. Even so, information on the health risks of these substances is limited to a number of case reports that are complicated by confounders such as analytical difficulties, mislabelling of drugs, concomitant exposures and interindividual differences., Conclusion: To aid in early legislation, data on clinical effects from poisons centres and user fora should be combined with (in vitro) screening methods and collaboration on an (inter)national level is essential. As a result, potentially hazardous NPS could be detected more quickly, thereby protecting public health., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

Introduction: Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates., Objective: This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants in humans., Methods: PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amfetamines, opioid analgesics and antidepressants. amfetamines. While some in vitro studies suggest that CYP2D6-mediated metabolites of 3,4-methylenedioxymethamfetamine (MDMA) are substantially more cytotoxic compared with unchanged MDMA, it is not yet confirmed in human cases of MDMA intoxication that extensive/ultra-rapid CYP2D6 metabolisers could be at higher risk. This would also apply to methamfetamine exposure and the related cardiac and central nervous system toxicity. Opioid analgesics. CYP2D6 ultra-rapid metabolisers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. Antidepressants. CYP2D6 poor metabolisers are generally more prone to adverse effects. Among them, the four drugs with the highest level of evidence are amitriptyline, nortriptyline, venlafaxine and fluoxetine. Further data are needed, however, for doxepin and paroxetine, while citalopram adverse effects seem definitely less influenced by CYP2D6 genetic polymorphisms., Conclusions: Either poor or extensive/ultra-rapid CYP2D6 metabolisers may be exposed to toxic effects of amfetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.

The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Gαq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.

Amphetamine-like drugs are sympathomimetic agents with marked central and peripheral stimulant properties. Despite the street illegal drugs such as amphetamine and ecstasy, some amphetamine-like compounds are also legally marketed under medical prescription in the treatment of attention deficit-hyperactivity disorder (methylphenidate) and obesity/overweight (fenproporex and diethylpropione). However, similar with what happens with their illicit analogues, therapeutic amphetamine-like drugs also share important toxicological risks. Although methylphenidate is considered the first choice in the treatment of attention deficit-hyperactivity disorder, its high popularity among teenagers and children is raising concern in the medical community. Regarding weight-loss purposes, the use of amphetamine-like compounds are very controversial, though. Thus, the present review will address pharmacokinetic, pharmacodynamic, and toxicological aspects of amphetamine-like compounds used with therapeutic aims.

Background: The purpose of this study was to determine whether the act of in vivo urine dilution is a random phenomenon., Methods: The sample population was divided into 4 groups for each of the drugs tested. The groups are precreatinine normalization laboratory positive, precreatinine normalization laboratory negative, and postcreatinine normalization laboratory drug positive, and postcreatinine normalization laboratory drug negative. The nonparametric Kruskal-Wallis 1-way ANOVA by ranks with post hoc Mann-Whitney U testing Bonferroni adjustment was used to compare the mean urine creatinine concentration of each group., Results: The Kruskal-Wallis test revealed that each drug had a statistically significant difference in group comparisons. Post hoc testing found that cocaine demonstrated no statistically significant difference between the prenormalization drug positive and negative groups. Amphetamines, marijuana, and opiates did confirm statistically significant differences between the prenormalization drug positive and negative groups. The examination of phencyclidine was limited by the lack of a prenormalization drug positive group; therefore, no definitive findings can be presented. Statistically significant differences were found between the postnormalization drug positive and negative groups for each drug tested., Conclusions: This study supports the theory that urine dilution is not a random happening and it may adversely affect the integrity of the drug-testing process.

Background: Fenproporex hydrochloride (FEN) is an anorectic drug used in the treatment of obesity, and its major metabolite is amphetamine (AMP), another central nervous system stimulant. The concentration versus time profile of FEN and its metabolite AMP has been described in classic biological matrices such as plasma and urine; however, there are no reports of such data in oral fluid., Objective: The aim of this study is to describe the pharmacokinetics of FEN and AMP in oral fluid after intake of FEN., Methods: Twenty-five milligrams of FEN (1 capsule of Desobesi-m) was orally administered to 6 male volunteers, and oral fluid samples were collected with a Quantisal device during 24.00 hours after drug ingestion. These samples were submitted to solid-phase microextraction before analysis by gas chromatography-mass spectrometry in the selected-ion-monitoring mode, using deuterium-labeled AMP as internal standard., Results: After FEN administration, both analytes could be detected in oral fluid of all volunteers with an initial detection time varying from 0.50 to 1.00 hour. FEN peak concentrations occurred between 1.00 and 1.50 hours after administration and were between 70.7 and 227.5 μg/L. For AMP, peak concentration occurred between 1.50 and 4.00 hours, reaching 33.0-150.9 μg/L., Conclusion: The authors observed that oral administration of FEN resulted in significant amounts of FEN and AMP in oral fluid, showing that oral fluid could be a biological matrix suitable for pharmacokinetic studies for both analytes. Using a compartmental approach, FEN data were best fitted by 1-compartment model with first-order input and output, whereas AMP followed a 2-compartment model with first-order input and output.

Introduction: Psychostimulants (methylphenidate and amphetamines) are the drugs of first choice in the pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD)., Objective: We summarize the pharmacological characteristics of amphetamines and compare them with methylphenidate, special emphasis being given to a comparison of effects and side effects of the two substances. Finally, we analyze the abuse and addiction risks., Methods: Publications were chosen based on a Medline analysis for controlled studies and meta-analyses published between 1980 and 2011; keywords were amphetamine, amphetamine salts, lisdexamphetamine, controlled studies, and metaanalyses., Results and Discussion: Amphetamines generally exhibit some pharmacologic similarities with methylphenidate. However, besides inhibiting dopamine reuptake amphetamines also cause the release of monoamines. Moreover, plasma half-life is significantly prolonged. The clinical efficacy and tolerability of amphetamines is comparable to methylphenidate. Amphetamines can therefore be used if the individual response to methylphenidate or tolerability is insufficient before switching to a nonstimulant substance, thus improving the total response rate to psychostimulant treatment. Because of the high abuse potential of amphetamines, especially in adults, the prodrug lisdexamphetamine (Vyvanse) could become an effective treatment alternative. Available study data suggest a combination of high clinical effect size with a beneficial pharmacokinetic profile and a reduced abuse risk., Conclusions: In addition to methylphenidate, amphetamines serve as important complements in the psychostimulant treatment of ADHD. Future studies should focus on a differential comparison of the two substances with regard to their effects on different core symptom constellations and the presence of various comorbidities.

Introduction: Pharmacotherapy is frequently used to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioral disorder of childhood. The typically prescribed agents for ADHD have varying durations of effect and degrees of efficacy. The broad range of pharmacological treatments available allows for both single and combination therapies for achieving optimal therapeutic effects. Metabolic, toxicological, and safety information are critical for an informed evaluation of the risk/benefit considerations in prescribing practices., Areas Covered: This article focuses on the medications with current FDA approval for use in the treatment of ADHD in pediatric and adult populations. This review covers the stimulants (amphetamine and methylphenidate) and non-stimulants (atomoxetine, clonidine extended release, and guanfacine extended release) used to treat ADHD and presents an overview of their respective metabolic, toxicological, and safety features. A literature search and review of the relevant medications were carried out using the PubMed database up to November 2011., Expert Opinion: New trends in study design based on drug profiles include the use of adjuvant therapies and the inclusion of patients with comorbidities. The recent expansion of inclusion/exclusion criteria in pediatric clinical trials of ADHD allows for a more rigorous analysis of associated benefits and risks with the use of adjuvant therapy.

The aim of the present study is to test a hypothesis that 5-HT(1A) and 5-HT(2C) receptors in the amygdala play an important role in the regulation of anxiety behaviors. We examined alterations in anxiety-like behaviors after manipulation of the expression of 5-HT(1A) and 5-HT(2C) receptors in the amygdala using recombinant adenovirus approaches. Recombinant adenoviruses containing a 5-HT(1A) promoter-controlled 5-HT(1A) antisense sequence or a 5-HT(2C) promoter-controlled 5-HT(2C) sense sequence were injected into the amygdala. Elevated plus-maze (EPM) and open field tests were conducted to determine anxiety-like behavior and locomotor activity. Reductions in the expression of 5-HT(1A) receptors in the amygdala significantly attenuated the time spent in the open arms of EPM and time spent in the center of an open field. Reduction in the percent of time spent in the open arms of EPM is negatively correlated with the density of 5-HT(1A) receptors in the central amygdala. On the other hand, increased expression of 5-HT(2C) receptors reduced the time spent in the open arms of EPM and time spent in the center of an open field. The reductions in the time spent and distance traveled in the open arms of EPM were correlated to the density of 5-HT(2C) receptors in the basolateral nucleus of amygdala. These data suggest that amygdaloid 5-HT(1A) receptors produce anxiolytic and 5-HT(2C) receptors produce anxiogenic effects. Together, the present results demonstrate the important role of the amygdaloid 5-HT(1A) and 5-HT(2C) receptors in the regulation of anxiety-like behaviors. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Amphetamine-type stimulants (ATS) such as methamphetamine are widely abused and can cause toxic effects in the body. In this study, a simple and accurate analytical method for distribution measurement of drugs in organs was developed to visualize localization of ATS in organs and to complement drug distribution by mass spectrometry imaging (MSI). The brain, liver and kidney from rats to which ATS had been administered were segmented into blocks of 2×2×2 mm3 at -30°C. Each organ block was micropulverized with a stainless-steel bullet at -80°C. The concentrations of drugs in each block were measured by liquid chromatography/tandem mass spectrometry. The three-dimensional distribution of drugs in a whole organ was expressed using color gradation of drug concentration after reconstruction of all blocks to the original locations. The distribution was also compared with that obtained by MSI. This method enabled measurement of drug distribution in organs with simple and clean procedures and accurate quantification unlike autoradiography and MSI. The methamphetamine concentrations were different between parts in an organ, particularly in the kidney. This method could be applicable to the measurement of the distribution of compounds in various solid samples and could be used as a complementary method for the measurement of the distribution of compounds by MSI., (Copyright © 2011 John Wiley & Sons, Ltd.)

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

p-Methoxymethamphetamine (PMMA) is an illegal psychedelic drug of abuse derived from an amphetamine structure with a risk to health and reports of several cases of intoxications and fatalities caused by its ingestion. However, its pharmacokinetics based on a controlled study is unknown and only partial information on its biotransformation in animal models is available. Our experimental design aimed to study the disposition and kinetic profile of PMMA and its metabolites in rat plasma and selected tissues after the bolus subcutaneous dose of 40mg/kg, using a GC-MS method. Prior to this, we performed a qualitative verification of its metabolites appearing in excreted urine fractions. PMMA maximum plasma concentration of 4014+/-1122ng/mL was reached 30min after dosing, whereas the appearance of metabolites was rather delayed. The disposition of PMMA was characterized by its approximate half-life of 1.0h, volume of distribution of 6.4L/kg and plasma clearance of 4.4L/h. PMMA tissue concentration exceeded plasma and the highest one was found in the lungs (c(max) 42,988+/-10,223ng/g). Penetration through the blood/brain barrier was more efficient considering PMMA and its N-desmethylated metabolite PMA (para-methoxyamphetamine) than hydroxylated metabolites. The maximum brain/plasma ratio value of PMMA (15.8) and PMA (11.8) was reached after 8h of observation. The experimental results ascertained could be useful for subsequent evaluation of the psychotropic or neurotoxic effects of PMMA and for diagnostic concern of intoxication.

The aim of this work was to develop and validate a method for analysing amphetamine-type stimulants (ATSs) and their metabolites in plasma, urine and bile by liquid chromatography with a strong cation-exchange column-tandem mass spectrometry, and to apply it to the pharmacokinetic study of ATSs. 3,4-Methylenedioxymethamphetamine, methamphetamine, ketamine and their main metabolites, 4-hydroxy-3-methoxymethamphetamine, 3,4-methylenedioxyamphetamine, p-hydroxymethamphetamine, amphetamine and norketamine, were simultaneously quantified by the new method (50-5000 ng/ml). The coefficients of variation and the percent deviations for the eight compounds were in the range of 0.2 to 5.3% and -9.4 to +12.8%, respectively. The recoveries were over 90% in all biological samples tested. This method was effective for the separation and the identification of ATSs and their main metabolites having amine moieties in plasma, urine and bile, and was applicable to pharmacokinetic analysis of methamphetamine, ketamine and their main metabolites in biological samples. This analytical method should be useful for the pharmacokinetic analysis of ATSs.

A panel of experts from several European countries has accomplished a systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder. Based on this analysis detailed recommendations about the use of these drugs in practice have been developed: (1) Long-acting preparations should be licensed and used; (2) They should not completely replace short-acting drugs (which will be the initial treatment for many children in view of cost and the greater flexibility of dosing). Individual clinical choices are necessary. (3) Both ATX and extended-release stimulants should be available. In addition, detailed recommendations will be made with regard to the criteria to be applied in choosing a preparation for the individual patient.

Objective: To compare the single-dose pharmacokinetics of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation, with MAS extended release (MAS XR) (Adderall XR) + MAS immediate release (MAS IR) administered 8 h later., Methods: This was a phase I, randomized, open-label, single-dose, single-center, two-period, crossover study in healthy adult volunteers designed to evaluate the bioavailability of triple-bead MAS over the course of a full day. Subjects were randomized to triple-bead MAS 37.5 mg or MAS XR 25 mg + MAS IR 12.5 mg administered 8 h later (MAS XR + MAS IR). The reference treatment was designed to mimic the clinical practice of providing extended coverage by supplementing a morning dose of MAS XR with a dose of MAS IR 8 h later in order to increase the duration of action. Plasma was assayed for d-amphetamine and l-amphetamine. Treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and laboratory data were also collected for safety evaluation., Results: Exposure to d- and l-amphetamine was equivalent between triple-bead MAS and MAS XR + MAS IR based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). For Cmax, least-squares mean ratios comparing triple-bead MAS with MAS XR + MAS IR were 101.0% and 90.9% for d-amphetamine and l-amphetamine, respectively, and for AUC(0-infinity) were 104.4% and 95.3% for d-amphetamine and l-amphetamine, respectively. Median time to maximum observed plasma concentration (Tmax) values for d-amphetamine and l-amphetamine were 8.0 h for triple-bead MAS and 10.0 h for MAS XR + MAS IR. There were no clinically meaningful differences between the study formulations for TEAEs or laboratory values. One subject experienced an ECG abnormality (asymptomatic premature ventricular contractions) leading to early termination from the study., Conclusions: In healthy adults, the exposure observed with triple-bead MAS 37.5 mg was bioequivalent to MAS XR 25 mg supplemented by MAS IR 12.5 mg administered 8 h later. These data demonstrate that a single morning dose of triple-bead MAS provides equivalent plasma concentrations to those observed with a dose-augmentation strategy of MAS XR in the morning followed by MAS IR in the afternoon, while minimizing peak-to-trough fluctuations. Triple-bead MAS was also generally well-tolerated in this study.

14C-acetate is preferentially taken up by astrocytes, and is a useful tool for measurement of glial metabolism. The aim of this study was to determine the effects of short-term ischemia on 14C-acetate uptake in the rat brain. The middle cerebral artery was occluded for 3, 10, or 30 minutes. Five minutes after reperfusion, rats were injected with 14C-acetate and decapitated 5 minutes later. Radioactivity concentrations in striatum and cerebral cortex were determined by autoradiography. Cerebral blood flow was also measured using 14C-iodoamphetamine. Neuronal cell death was measured by Nissl staining, and expression of monocarboxylate transporter-1 was examined by immunohistochemical staining. A significant reduction of 14C-acetate uptake was observed in striatum by 3 minutes of occlusion. The degree of reduction of 14C-acetate uptake and reduction area were increased with occlusion period. In contrast, within the same region the regional blood flow was increased by 10 minutes of occlusion, suggesting that uptake of 14C-acetate was independent of blood flow. No neural cell death was detected, and no significant alteration of monocarboxylate transporter-1 expression was observed by 30 minutes of occlusion. These results indicate that 14C-acetate uptake is a sensitive marker for glial metabolism in the ischemic rat brain.

Paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) are methoxylated phenylethylamine derivatives that have been banned in Taiwan since December 2005. The case history and pathological and toxicological findings of eight recent PMMA fatalities were investigated. All specimens from these cases were initially identified by an AxSYM fluorescence polarization immunoassay screening test for amphetamines with a 300 ng/mL cutoff. Specimens screened positive were confirmed and quantitated by gas chromatography-mass spectrometry. The mean age of these PMMA-related fatalities was 18.9 +/- 4.4 years in the range of 14-25. Seven (87.5%) of these eight cases were men. The mean, standard deviation, and range of PMA found in the heart blood collected from these 8 cases were 0.213, 0.144, and 0.079-0.489 microg/mL, respectively. The corresponding data for PMMA were 4.312, 4.806, and 1.208-15.824 microg/mL, respectively. Other drugs, such as MDA, MDMA, ketamine, norketamine, hydroxymidazolam, methamphetamine, and pentobarbital, were also found in these cases.

(-)-Deprenyl is a selective irreversible inhibitor of MAO-B. The parent compound is responsible for the enzyme inhibitory effect, but its metabolites are also playing a role in the complex pharmacological activity of the substance. In the present studies male NMRI mice were treated orally, subcutaneously, intraperitoneally and intravenously with 5 mg/kg of (-)-deprenyl. The time related changes of the plasma concentrations of the parent compound and its main metabolites (methamphetamine, desmethyl-deprenyl and amphetamine) were determined by GC/ MSD technique. The main pharmacokinetic parameters (C(max), t(max), t1/2beta, AUC(0-6), AUC(0-infinity)) have been calculated. (-)-Deprenyl is well absorbed after oral and parental treatment. The peak concentrations (C(max)) were reached at 15 min after treatment and the absorption was followed by a fast elimination (t1/2beta < or = 2h). (-)-Deprenyl has an intensive "first pass" metabolism after oral treatment; only 25% of the parent compound reaches the systemic circulation. Increased bioavailability was detected after subcutaneous (87.1%) and intraperitoneal (78.7%) administration. The main metabolic pathway of (-)-deprenyl is the N-depropargylation, leading to the formation of methamphetamine. N-demethylation of (-)-deprenyl leads to formation of desmethyl-deprenyl. Amphetamine is produced from both former metabolites. After oral treatment the plasma concentrations of methamphetamine are higher during the first 6 h than that of (-)-deprenyl, while the opposite was found after parental treatment. The results indicate, that (-)-deprenyl, a potent MAO-B inhibitor, might induce a different spectrum of activity (e.g. antidepressant), when it is administered parenterally (transdermally). The new spectrum can be due to the special pharmacokinetic behaviour of the inhibitor.

Effects of gastrointestinal transit on plasma concentrations of drugs from mixed immediate-release and enteric-coated pellet formulation were simulated with models developed by including gastric emptying time and lag time of emptying. Models were evaluated by comparing simulated plasma concentrations of amphetamine from Monte Carlo simulations to available published data of a commercial mixed pellet formulation (Adderall XR). Results show that the plasma profile from the mixed pellet formulation does not mimic that from two immediate-release doses administered at different times. Instead, the plasma profile from the mixed pellets of amphetamine is similar to a typical sustained-release formulation. The pharmacokinetic models presented herein describe plasma concentrations of amphetamine from mixed pellet formulation quite well. The models and assumptions are general and can be applied to other drugs in similar mixed pellet dosage forms.

"Ice", "crystal meth", is the smokable form of methamphetamine hydrochloride. This paper will comment on the pharmacological, epidemiological, clinical and social issues related to smoking the drug as opposed to either its injection or ingestion. Furthermore, some data related to amphetamines/methamphetamines consumption, request for treatment, seizures, related offences and deaths in the UK (1990-2002) will be offered here. Peak rates, for most indicators, were reached at the end of the '90s, to fall down in the following years. The only indicator which seemed not to show any declining rates is number of deaths, but this may be related to a more general increase in stimulant death rates recently observed in the UK. It is argued that methamphetamines, and particularly "crystal meth", could reach the same prevalence levels of use in the UK as it is already in the US but recent reclassification of the drug to Class A in the UK could help to better control this emerging issue.

We previously reported that treatment and withdrawal from cocaine increases: (1) 5-HT2A receptor-mediated neuroendocrine responses, and (2) Galphaq and Galpha11 G-protein levels in the hypothalamic paraventricular nucleus (PVN) at 48 h post-treatment. This study investigates changes in the initial 24 h of withdrawal to discern whether 5-HT2A receptor supersensitivity is due to cocaine treatment or is induced during the withdrawal period. We report here increases in 5-HT2A receptor-mediated neuroendocrine responses only 12 or 24 h post-treatment, but not during the initial 4 h withdrawal period. Levels of membrane- or cytosol-associated Galphaq or Galpha11 proteins in PVN are not altered during the first 24 h of withdrawal. However, the density of 125I-(-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI)-labeled high-affinity 5-HT2A receptors in PVN increased 35% in rats withdrawn from cocaine for 24 h. These findings demonstrate that cocaine-induced increases in 5-HT2A receptor function in PVN represents a withdrawal-induced phenomena that: (1) is likely attributed to increased G-protein coupled/high-affinity conformational state of the 5-HT2A receptor, and (2) occurs in the absence of changes in the levels of associated G proteins during the first 24 h.

Serotonin 2A (5-HT2A) receptors are coupled to Galphaq and Galpha11 proteins to activate phospholipase C (PLC). Regulators of G-protein signaling proteins (RGS) modulate G-protein signaling by accelerating the intrinsic GTPase activity of Galphaq and Galpha11. This study investigated the effects of over-expression of wild-type Galphaq proteins (Gq-Tg) and over-expression of RGS-insensitive Galphaq proteins (G188S, RGSi-Tg) on 5-HT2A receptor mediated signaling in transgenic rats. Over-expression of wild-type Galphaq and RGS insensitive mutant Galphaq did not produce significant alterations in the levels of Galpha11, RGS2, RGS4, RGS7, RGS16 or 5-HT2A proteins. RGSi-Tg rats had higher oxytocin and corticosterone responses to (-)DOI, a 5-HT2A/2C receptor agonist, compared to Gq-Tg rats. RGSi-Tg and Gq-Tg rats had higher ACTH responses to (-)DOI compared to control rats. Similarly, 5-HT-stimulated PLC activity in the frontal cortex was higher in RGSi-Tg and Gq-Tg rats compared to control rats. In contrast, GTPgammaS-stimulated PLC activity was higher in Gq-Tg rats but not in RGSi-Tg rats compared to control rats. There was a small but statistically significant increase in the affinity of [125I]-DOI labeled 5-HT2A receptors in RGSi-Tg rats and Gq-Tg rats compared to controls. There were no significant differences in Bmax and Kd of [3H] ketanserin labeled 5-HT2A receptors among the three groups. These data suggest that the effect of RGS proteins on 5-HT2A receptor signaling is cell type specific. In transgenic rats over-expressing Galphaq, endogenous RGS proteins have a negative effect on 5-HT2A receptor-mediated oxytocin release. In contrast, endogenous RGS protein had no impact on 5-HT2A receptor-mediated ACTH release in transgenic rats.

Objectives: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20, 40, and 60 mg., Methods: Study A, an open-label single-period study, and Study B, a randomized, open-label, three-way crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20, 40, and 60 mg separated by 7-14-day washout periods., Findings: Plasma dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of d-amphetamine to l-amphetamine was observed for AUC0-inf and Cmax. Tmax was 4.2 and 4.3 hours for d-amphetamine to l-amphetamine, respectively. In Study B, for d- and l-amphetamine, statistically significant differences were observed for AUC0-t, AUC0-inf, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5-5.3 hours) with all given MAS XR doses., Conclusion: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of d-amphetamine to l-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Stimulant medications have proven to be effective in reducing the core symptoms of hyperactivity, impulsivity and inattention and are considered the first line of therapy for patients with attention-deficit/hyperactivity disorder (ADHD). Mixed amphetamine salts extended-release capsules (MAS XR; Adderall XR, Shire Pharmaceuticals Group) include immediate-release pellets of mixed amphetamine salts that release the first half of the dose upon ingestion and delayed-release pellets that begin to release active drug approximately 4 h later. The MAS XR capsule contains the same 3:1 ratio of dextroamphetamine to levoamphetamine as do mixed amphetamine salts immediate-release tablets (MAS IR; Adderall), Shire Pharmaceuticals Group), and the bioavailability and pharmacokinetic profiles of MAS XR 20 mg are comparable to those with MAS IR 10 mg b.i.d. MAS XR has a rapid onset of action--within 1.5 h--and provides 12 h coverage. The efficacy, safety and extended duration of action of MAS XR have been established through clinical studies in school-age children, adolescents and adults.

Interpretation of drug testing results requires detailed scientific information, particularly in those cases where the question of legitimate use versus illicit use arises. Amphetamine remains a widely abused drug throughout the world, although it is also used therapeutically for weight loss, narcolepsy, and attention-deficit disorder with hyperactivity (ADHD). Treatment of ADHD using stimulant drugs is much more common now than it was in even the recent past. Increasingly, older individuals are diagnosed and treated for ADHD, and treatment often continues into adulthood. Amphetamine is commonly used for the treatment of ADHD and is available by prescription as either the d-enantiomer or a mixture of enantiomers. Although used for many years, there are no data available to describe the excretion profile of amphetamine and its enantiomers following repeated use of the drug. As a result, medical review officers (MROs) and forensic toxicologists have no direct evidence to base their decisions on when it comes to evaluation of use of these drugs. The current study was designed to determine the concentration and enantiomer excretion profile following repeated daily administration of mixed enantiomers of amphetamine. Twenty milligrams of Adderall was administered daily to five healthy subjects with all subsequent ad lib urine samples collected for at least five days following administration of the five-dose regimen. Adderall is a 3:1 mixture of d- and l-enantiomers of amphetamine salts and represents the mixed enantiomer proportion of amphetamine available in the United States through pharmaceutical channels. Peak amphetamine concentrations ranged from 5739 to 19,172 ng/mL. Samples containing > or = 500 ng/mL amphetamine (the administrative cutoff for a positive result by gas chromatography-mass spectrometry) were seen up to 60:15 (h:min) following administration of the last dose. Enantiomer analysis showed the d-enantiomer to be in excess of the l-enantiomer for as long as the drug was administered. After administration of the last dose of drug, the proportion of l-enantiomer increased over time. Not all samples that contained > or = 500 ng/mL total amphetamine were positive when tested by immunoassay because of the differing cross-reactivity of the enantiomers. This study provides the first description of the excretion of amphetamine following repeated administration of Adderall. The presence of the l-enantiomer separates this drug from other formulations composed of only the d-enantiomer (i.e., Dexedrine and much illicit amphetamine), thus readily differentiating them from Adderall use. Some illicit and medicinal amphetamine is, however, a mixture of amphetamine enantiomers. Because the enantiomers are metabolized at different rates, their proportion offers the opportunity to describe excretion versus time. Coupling this data with drug concentration makes it possible for forensic toxicologists and MROs to come to an informed decision regarding the involvement of this drug in a positive drug test result.

Excessive daytime sleepiness (EDS) has recognized detrimental consequences such as road traffic accidents, impaired psychological functioning and reduced work performance. EDS can result from multiple causes such as sleep deprivation, sleep fragmentation, neurological, psychiatric and circadian rhythm disorders. Treating the underlying cause of EDS remains the mainstay of therapy but in those who continue to be excessively sleepy, further treatment may be warranted. Traditionally, the amphetamine derivatives, methylphenidate and pemoline (collectively sympathomimetic) psychostimulants were the commonest form of therapy for EDS, particularly in conditions such as narcolepsy. More recently, the advent of modafinil has broadened the range of therapeutic options. Modafinil has a safer side-effect profile and as a result, interest in this drug for the management of EDS in other disorders, as well as narcolepsy, has increased considerably. There is a growing school of thought that modafinil may have a role to play in other indications such as obstructive sleep apnea/hypopnea syndrome already treated by nasal continuous positive airway pressure but persisting EDS, shift work sleep disorders, neurological causes of sleepiness, and healthy adults performing sustained operations, particularly those in the military. However, until adequately powered randomised-controlled trials confirm long-term efficacy and safety, the recommendation of wakefulness promoters in healthy adults cannot be justified.

Toxicological evaluation of postmortem samples collected from a pilot involved in a unique fatal civil aircraft accident is described in this paper. A one-occupant airplane was substantially damaged upon colliding with terrain in poor visibility. Remains of the pilot were found outside the aircraft. Pathological examination revealed multiple blunt force injuries and vascular congestion. The fluorescence polarization immunoassay disclosed 8.0 microg/mL amphetamines in urine. Gas chromatographic/mass spectrometric analyses determined the presence of methamphetamine (1.13 microg/mL in blood and 59.2 microg/mL in urine) and amphetamine (0.022 microg/mL in blood and 1.50 microg/mL in urine). Methamphetamine was distributed throughout the body, including the brain. The amount of methamphetamine in gastric contents was 575-fold higher than that of amphetamine. The (+)- and (-)-forms of methamphetamine were present in equal proportions in gastric contents. The methamphetamine concentration found in blood was in the range sufficient to produce toxic effects, causing performance impairment.

Conducting toxicology on post-mortem specimens provides a number of very significant challenges to the scientist. The range of additional specimens include tissues such as decomposing blood and other tissues, hair, muscle, fat, lung, and even larvae feeding on the host require special techniques to isolate a foreign substance and allow detection without interference from the matrix. A number of drugs of abuse are unstable in the post-mortem environment that requires careful consideration when trying to interpret their significance. Heroin, morphine glucuronides, cocaine and the benzodiazepines are particularly prone to degradation. Moreover, redistributive process can significantly alter the concentration of drugs, particularly those with a higher tissue concentration than the surrounding blood. The designer amphetamines, methadone and other potent opioids will increase their concentration in blood post-mortem. These processes together with the development of tolerance means that no concentration of a drug of abuse can be interpreted in isolation without a thorough examination of the relevant circumstances and after the conduct of a post-mortem to eliminate or corroborate relevant factors that could impact on the drug concentration and the possible effect of a substance on the body. This article reviews particular toxicological issues associated with the more common drugs of abuse such as the amphetamines, cannabinoids, cocaine, opioids and the benzodiazepines.

Designer drugs of the amphetamine type (eg, MDMA, MDEA, MDA), of the new benzyl or phenyl piperazine type (eg, BZP, MDBP, mCPP, TFMPP, MeOPP), or of the pyrrolidinophenone type (eg, PPP, MOPPP, MDPPP, MPPP, MPHP) have gained popularity and notoriety as rave drugs. These drugs produce feelings of euphoria and energy and a desire to socialize. Although in the corresponding drug scene designer drugs have the reputation of being safe, studies in rats and primates in combination with human epidemiologic investigations indicate potential risks to humans. Thus, a variety of adverse effects have been associated with the use/abuse of this class of drugs in humans, including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, and psychopathology. Metabolites were suspected to contribute to some of the toxic effects. Therefore, knowledge of the metabolism is a prerequisite for toxicologic risk assessment. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are described for designer drugs of different groups. In summary, polymorphically expressed CYP2D6 was the major enzyme catalyzing the major metabolic steps of the studied piperazine- and pyrrolidinophenone-derived designer drugs. However, it cannot be concluded at the moment whether this genetic polymorphism is of clinical relevance.

Several cases of death associated with 4-methylthioamphetamine (4-MTA) have raised public concern about the abuse of this designer drug that is usually sold as "Ecstasy" or "Flatliners". Since only very little is known about the metabolism of 4-MTA in humans we performed an in vitro study incubating racemic 4-MTA with primary hepatocytes isolated from three male human donors. Additionally, hepatocytes from male monkey (Cynomolgus), dog (Beagle), rabbit (Chinchilla), rat (Sprague-Dawley), and mouse (CD1) were examined for the metabolism of racemic 4-MTA. We observed that 4-MTA was not extensively metabolised by hepatocytes from all species examined. The main metabolite was identified as 4-methylthiobenzoic acid which, for the first time has been described as a human metabolite. In addition to metabolism we also examined 4-MTA-induced toxicity as evidenced by the ATP cellular content. Interestingly, one of the three human donors showed a dramatically increased sensitivity to the reduction in ATP content induced by 4-MTA. Comparing the species examined, the most extensive formation of 4-methylthiobenzoic acid was observed in the rabbit hepatocytes followed by human, monkey, dog and mouse hepatocytes, whereas no formation of 4-methylthiobenzoic acid was seen in the rat hepatocytes. Toxicity data suggest that rabbit hepatocytes are more resistant to 4-MTA than the other species, which may be due to the more extensive metabolism. In conclusion, we have shown that 4-methylthiobenzoic acid is the main metabolite formed from 4-MTA by human hepatocytes and also by the hepatocytes of the other tested species except the rat. Toxicity data suggest only moderate interspecies differences.

There are increasing numbers of deaths related to taking MDMA, MDE and PMA reported where the deceased typically took several different drugs with these compounds. Hence, mutual modulation of the pharmacokinetics in drug combinations with "ecstasy" might be a risk factor for "ecstasy"-related morbidity. Regarding potential drug - drug interactions, there are no data evaluating a possible contribution of the multidrug resistance transporter P-glycoprotein (Pgp) in contrast to the cytochrome P450 enzyme system. Therefore, individual "ecstasy" compounds have been tested for their ability to interact with Pgp using a fluorometric calcein assay as a model for Pgp inhibition in porcine kidney epithelial cells with overexpression of human Pgp (L-MDR1). All three compounds increased calcein retention in L-MDR1 cells in a concentration-dependent manner, with MDE being the most potent and MDMA the weakest Pgp inhibitor. The effective concentrations were 1 - 3 orders of magnitude higher than plasma concentrations observed in vivo, suggesting that these compounds are only weak inhibitors of Pgp, which is unlikely to influence the access of other compounds to the brain. However, it cannot be excluded that co-administration of Pgp inhibitors such as ritonavir or paroxetine could increase MDMA, MDE and PMA bioavailability and also enhance brain entry leading to severe side effects.