Enantiomer-specific analysis of amphetamine in urine, oral fluid and blood.

Illegal amphetamine is usually composed of a racemic mixture of the two enantiomers (S)- and (R)-amphetamine. However, when amphetamine is used in medical treatment, the more potent (S)-amphetamine enantiomer is used. Enantiomer-specific analysis of (S)- and (R)-amphetamine is therefore used to separate legal medical use from illegal recreational use. The aim of the present study was to describe our experience with enantiomer-specific analysis of amphetamine in urine and oral fluid, as well as blood, and examine whether the distribution of the two enantiomers seems to be the same in different matrices. We investigated 1,722 urine samples and 1,977 oral fluid samples from prison inmates, and 652 blood samples from suspected drugged drivers, where prescription of amphetamine was reported. Analyses were performed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS). The enantiomer separation was achieved by using a chiral column, and results from the method validation are reported. Samples containing <60% (S)-amphetamine were interpreted as representing illegal use of amphetamine. The distribution of the two enantiomers was compared between different matrices. In urine and oral fluid, the mean amount of (S)-amphetamine was 45.2 and 43.7%, respectively, while in blood, the mean amount of (S)-amphetamine was 45.8%. There was no statistically significant difference in the amount of (S)-amphetamine between urine and oral fluid samples and between urine and blood samples, but the difference was significant in blood compared to oral fluid samples (P < 0.001). Comparison of urine and oral fluid between similar populations indicated that enantiomers of amphetamine can be interpreted in the same way, although marginally higher amounts of (R)-amphetamine may occur in oral fluid. Oral fluid, having several advantages, especially during collection, could be a preferred matrix in testing for illegal amphetamine intake in users of medical amphetamine.

Enantiomeric profile of amphetamines in seized drug samples and in blood of impaired drivers in Iceland: The rise of (R)-methamphetamine?

Amphetamine (AMP) and methamphetamine (METH) use is increasing globally. Illegal AMP is generally a racemic mixture, whereas AMP-containing attention-deficit hyperactivity disorder drugs prescribed in Iceland consist of S-AMP. AMP is also a main metabolite of interest after METH intake. Distinguishing between legal and illegal AMP intake is vital in forensic toxicology. A chiral UPLC-MS-MS method was used to determine the enantiomeric profile of AMP and METH in circulation in Iceland by analysing blood samples from drivers suspected of driving under the influence of drugs (DUID) and seized drug samples from 2021 and 2022. All seized AMP samples (n = 48) were racemic, whereas all but one seized METH sample (n = 26) were enantiopure. Surprisingly, a large portion of the enantiopure METH samples was R-METH. DUID blood samples positive for AMP (n = 564) had a median blood concentration of 180 ng/mL (range 20-2770 ng/mL) and a median enantiomeric fraction (EFR) of 0.54 (range 0-0.73), whereas samples positive for METH (n = 236) had a median blood concentration of 185 ng/mL (range 20-2300 ng/mL) and a median EFR of 0.23 (range 0-1). The findings of this study show a significantly lower blood concentration in drivers with only S-AMP detected compared with when the R-isomer is also detected. No significant difference in blood concentration was detected between the sample groups containing S-METH, R-METH or both enantiomers. The occurrence of R-METH in both seized drug samples and DUID cases indicates a change in drug supply and a need for better scientific knowledge on R-METH abuse.

A two-year review of cocaine findings in impaired driving investigations in Ontario, Canada.

Drug-impaired driving is an increasing public safety concern across Canada, particularly due to the demonstrated increase in use of recreational drugs such as cocaine. Cocaine is a central nervous system stimulant drug; however, it can impair an individual's driving ability in both the stimulant and crash phases. Despite the scientific consensus regarding cocaine's potential for driving impairment, there is relatively little information available regarding blood concentrations and associated observations of impairment in suspected impaired drivers. Retrospective data analysis was performed to evaluate suspected impaired driving cases in which cocaine and/or benzoylecgonine were detected alone, or in combination with other drugs, in blood and urine samples submitted to the Toxicology Section of the Centre of Forensic Sciences with incident dates between 2021 and 2022. Cocaine and/or benzoylecgonine were detected in 46% (blood) and 66% (urine) of the total impaired driving samples submitted. In 41 cases where cocaine and/or benzoylecgonine were the only drug finding in blood, concentrations of cocaine and benzoylecgonine ranged from 0.0073 to 0.26 mg/L (mean 0.096 mg/L) and 0.13 to 5.3 mg/L (mean 2.1 mg/L), respectively. Driving observations reported by the arresting officer in cases where cocaine and/or benzoylecgonine were the only drug finding in blood and urine included the driver being involved in a collision, the vehicle leaving the roadway, erratic driving and the driver being asleep at the wheel; observations of drug impairment reported by the drug recognition expert at the time of driver evaluation included abnormal speech patterns, poor balance/incoordination, abnormal body movements and the individual falling asleep. The results provide concentrations of cocaine and benzoylecgonine observed in suspected impaired drivers, insight into observations that may be associated with prior cocaine use and additional information to inform on the effects of cocaine on driving.

Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.

Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratioBSA) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.

Caffeine increases performance and leads to a cardioprotective effect during intense exercise in cyclists.

The present study was designed to investigate the effects of different caffeine dietary strategies to compare the impact on athletic performance and cardiac autonomic response. The order of the supplementation was randomly assigned: placebo(4-day)-placebo(acute)/PP, placebo(4-day)-caffeine(acute)/PC and caffeine(4-day)-caffeine(acute)/CC. Fourteen male recreationally-trained cyclists ingested capsules containing either placebo or caffeine (6 mg kg-1) for 4 days. On day 5 (acute), capsules containing placebo or caffeine (6 mg kg-1) were ingested 60 min before completing a 16 km time-trial (simulated cycling). CC and PC showed improvements in time (CC vs PP, Δ - 39.3 s and PC vs PP, Δ - 43.4 s; P = 0.00; ƞ2 = 0.33) and in output power (CC vs PP, Δ 5.55 w and PC vs PP, Δ 6.17 w; P = 0.00; ƞ2 = 0.30). At the final of the time-trial, CC and PC exhibited greater parasympathetic modulation (vagal tone) when compared to the PP condition (P < 0.00; ƞ2 = 0.92). Our study provided evidence that acute caffeine intake (6 mg∙kg-1) increased performance (time-trial) and demonstrated a relevant cardioprotective effect, through increased vagal tone.

Increasing age and methamphetamine use.

ANALYSIS: of autopsy files at Forensic Science SA was undertaken over a 20-year period (2000-2019) in five representative time periods to determine the average ages for all adults (≥18 years) where methamphetamine was detected. There were 239 cases with statistically significant increased mean ages over the time of the study ranging from 32.6yrs in 2000 to 42.2yrs in 2019 (p < 0.0001). Although methamphetamine use may be considered predominantly a feature of younger individuals this does not appear to be the case. Whether this apparent increase in the age of methamphetamine users was due to natural aging of methamphetamine users, an increase in use of methamphetamine by older individuals, or to an increased capture of older cases due to wider toxicological screening is uncertain. However, the importance of these results is to alert practitioners to the presence of methamphetamine use in older individuals which may predispose to death given the increased incidence of underlying cardiovascular diseases with age. In addition, in clinical settings there exists a cohort of older individuals who may be at risk of exacerbating their heart disease and precipitating cardiac events by using methamphetamine.

Intersecting minority statuses and tryptophan degradation among stimulant-using, sexual minority men living with HIV.

BACKGROUND: Disclosure of one's sexual orientation as a sexual-minority (SM) person (i.e., being "out") may affect HIV-related health outcomes. This longitudinal study examined whether race/ethnicity moderated effects of outness on the plasma kynurenine/tryptophan (KT) ratio, a marker of dysregulated serotonin metabolism due to immune activation that predicts clinical HIV progression. METHODS: Participants were African American, Hispanic/Latino, and non-Hispanic White, methamphetamine-using SM men living with HIV (N = 97) who completed self-report scales of outness and SM stress at baseline for a randomized controlled trial of a positive affect intervention. Linear mixed modeling was used to test whether race/ethnicity and experimental condition moderated the association of baseline outness with the KT ratio at baseline, 6, 12, and 15 months controlling for SM stress, sociodemographics, HIV disease markers, and recent stimulant use. RESULTS: The interactions of outness by race/ethnicity and outness by experimental condition on the KT ratio were significant. Greater outness predicted a lower KT ratio over time in non-Hispanic White SM men, but not among SM men of color (MOC). Greater outness predicted a lower KT ratio over time for SM men in the control, but not among those in the intervention arm. CONCLUSION: Being more out may be protective for non-Hispanic White SM men, but not for their SM MOC peers. Outness mattered for participants who did not receive the positive affect intervention. Findings underscore the potentially different contexts and consequences of outness depending on SM men's race/ethnicity and whether they received a positive affect intervention. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A sensitive HPLC-MS/MS method for the detection, resolution and quantitation of cathinone enantiomers in horse blood plasma and urine.

Resolution of cathinone enantiomers in equine anti-doping analysis is becoming more important to distinguish the inadvertent ingestion of plant-based products from those of deliberate administration of designer synthetic analogs. With this in mind, a rapid and sensitive method was developed and validated for the detection, resolution and quantitative determination of cathinone enantiomers in horse blood plasma and urine. The analytes were recovered from the blood plasma and urine matrices by using a liquid-liquid extraction after adjusting the pH to 9. The recovered analytes were derivatized with Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide, a chiral derivatizing agent analogous to Marfey's reagent. The resulting diastereoisomers were baseline resolved under a reversed-phase liquid chromatographic condition. Derivatization of the analytes not only allowed the separation of the enantiomers using cost-effective traditional liquid chromatography conditions and reversed-phase columns but also increased the sensitivity, at least to an order of magnitude, when tandem mass spectrometry is used for the detection. A limit of detection of 0.05 ng/mL was achieved for cathinone enantiomers for both matrices. Acceptable intraday and interday precision and accuracy along with satisfactory dilution accuracy and precision were observed during the method validation. The method suitability was tested using the post administration urine samples collected after single doses of cathinone and ephedrine as single-enantiomeric form and methcathinone as racemic form. Finally, a proof of concept of the isomeric ratio in urine samples to distinguish the presence of cathinone as a result of accidental ingestion of plant-based product from that of an illicit use of a designer product is demonstrated. To the best of our knowledge, this is the first such work where cathinone enantiomers were resolved and quantified in horse blood plasma and urine at sub nanogram levels.

Stability of synthetic cathinones in clinical and forensic toxicological analysis-Where are we now?

Understanding the stability of analyzed drugs in biological samples is a crucial part for an appropriate interpretation of the analytical findings. Synthetic cathinones, as psychoactive stimulants, belong to a major class of new psychoactive substances. As they are subject to several degradation pathways, they are known to clinical and forensic toxicologists as unstable analytes in biological samples. When interpreting analytical data of synthetic cathinones in biological samples, analysts must be aware that the concentration of analytes may not accurately reflect the levels at the time they were acquired owing to many factors. This review provides (i) an overview of the current scientific knowledge on the stability of synthetic cathinones and/or metabolites in various human biological samples with a focus on factors that may deteriorate their stability-such as storage temperature, length of storage, matrix, pH, type of preservatives, concentration of analytes, and the chemistry of the analytes-and (ii) possible solutions on how to avoid such degradation. The PubMed database as well as Google Scholar was thoroughly searched to find published studies on the stability of synthetic cathinones since 2007 by searching specific keywords. A total of 23 articles met the inclusion criteria and were included in this review. Synthetic cathinones that carry methylenedioxy or N-pyrrolidine ring showed higher degradation resistance over other substituted groups. Acidification of samples pH plays a crucial role at increasing the stability of cathinones even with analytes that were frequently considered as poorly stable. This review also provides several recommendations for best practice in planning the experimental design, preservation, and storage conditions in order to minimize synthetic cathinones' degradation in human biological samples.

Arrest-related death on the basis of a drug-induced excited delirium syndrome.

AIMS: In typical arrest-related death (ARD) scenarios, the victims often show signs of excited delirium syndrome (ExDS), intoxication, exhaustion and/or suffered from a preexisting physical or psychiatrical condition, all of which could have caused or at least triggered the person's death. Since autopsy findings are very rare in such cases, a clear clinicopathologic diagnosis and thus mechanism of death is rarely found. METHODS: We present a case of a 25-year old woman, who died while being arrested by the police. Based on the patient's medical history, autopsy findings, contradicting witness testimonies, and reliable clinical and toxicological blood parameters, the most probable diagnosis is discussed. RESULTS: The cause of death was determined as cardiac arrest subsequent to a combination of excited delirium syndrome, physical exhaustion and respiratory impairment. The manner of death was unnatural and juridically, the charges were dropped. CONCLUSIONS: In cases, where the cause and mechanism of death can only be diagnosed by exclusion, police collaboration, detailed clinical history (past and present) as well as clinical blood parameter analyses are necessary to help evaluating possible contributing factors and the most probable cause of death in ARD.

Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients.

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d-amphetamine concentrations from pediatric patients (6-17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d-amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d-amphetamine.

A Pharmacokinetic Study of Methylphenidate Hydrochloride Multilayer Extended-Release Capsules (Aptensio XR®) in Preschool-Aged Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH. METHODS: Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (Vd) data were compared with a historical group of older children aged 6-11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed. RESULTS: Mean dose-normalized Cmax and area under the curve to the last measurable observation (AUC0-t) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) for Cmax/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC0-t/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time to Cmax ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized Cmax concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6-11 years. Children aged 4 to < 6 years had a lower Vd than children aged 6-11 years. There were no unexpected safety signals. CONCLUSION: The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6-11 years, apart from a lower Vd and relatively higher systemic MPH levels for children in the preschool group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02470234.

Quantifying enhanced risk from alcohol and other factors in polysubstance-related deaths.

BACKGROUND: To quantify how alcohol, polysubstance use and other factors influence opioid concentrations in drug-related deaths in West Virginia (WV), United States. METHODS: Multiple linear regression models were employed to identify relationships among alcohol, other factors, and the concentrations of four commonly identified opioids (fentanyl, hydrocodone, oxycodone, methadone), accounting for demographic, toxicological and comorbid characteristics in WV drug-related deaths from 2005 to 2018. RESULTS: Alcohol concentrations of 0.08% or above were associated with significant reductions in blood concentrations of fentanyl (27.5%), hydrocodone (30.5%) and methadone (32.4%). Significantly lower predicted concentrations of all opioids studied were associated with multiple opioid vs. single opioid presence, with predicted concentration reductions ranging from 13.7% for fentanyl to 65-66% for hydrocodone and oxycodone. Benzodiazepine presence was associated with small, non-statistically significant changes in opioid concentrations, while stimulant presence was associated with statistically significant reductions in hydrocodone and oxycodone concentrations. CONCLUSIONS: Co-ingestion of alcohol, multiple opioids or stimulants were associated with significantly decreased predicted concentrations of commonly identified opioids in drug deaths. Further evidence is provided for enhanced risks from polysubstance use with opioids, which has important public health implications.

Enantiomeric separation and quantification of R/S-amphetamine in serum using semi-automated liquid-liquid extraction and ultra-high performance supercritical fluid chromatography-tandem mass spectrometry.

The amphetamine molecule contains a chiral center and its enantiomers exhibit differences in pharmacological effects, with the S-enantiomer mediating most of the central nervous system stimulating activity. The majority of prescribed amphetamine consists of the pure S-enantiomer, but therapeutic formulations containing the R-enantiomer in various proportions are also available. Illegal amphetamine remains available mainly as a racemic mixture of the R- and S-enantiomers. To distinguish between legal and illegal consumption of amphetamine a method for enantiomeric separation and quantification of R/S-amphetamine in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was performed by a semi-automated liquid-liquid extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO2 and 0.1% ammonium hydroxide in 2-propanol/methanol (50/50, v/v). The injection volume was 2 µL and run time was 4 minutes. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 12.5-1,000 nM for each analyte. The between-assay relative standard deviations were in the range of 1.3-3.0%. Recovery was 73% and matrix effects ranged from 95 to 100% when corrected with internal standard. After development and validation, the method has been successfully implemented in our laboratory for both separation and quantification of R/S-amphetamine and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples.

Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs.

Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11ß-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.

Dose-Related Concentrations of Neuroactive/Psychoactive Drugs Expected in Blood of Children and Adolescents.

PURPOSE: Therapeutic drug monitoring is highly recommended for children and adolescents treated with neurotropic/psychotropic drugs. For interpretation of therapeutic drug monitoring results, drug concentrations (C/D) expected in a "normal" population are helpful to identify pharmacokinetic abnormalities or nonadherence. Using dose-related concentration (DRC) factors obtained from pharmacokinetic data, C/D ranges expected under steady state can be easily calculated by multiplication of DRC by the daily dose. DRC factors, however, are defined only for adults so far. Therefore, it was the aim of this study to estimate DRC factors for children and adolescents and compare them with those of adults. METHODS: To obtain pharmacokinetic data (apparent total clearance of drugs from plasma after oral administration, elimination half-life, area under the curve, and minimum serum drug concentration) from children and adolescents treated with psychotropic drugs, a systematic review of published literature was performed, and the pharmaceutical companies that market these drugs were contacted. Available information was used for the calculation of DRC factors. RESULTS: Fourteen of 26 drugs had similar DRC factors to those reported for adults; 8 and 4 had higher and lower factors, respectively. The antidepressants citalopram, clomipramine, fluvoxamine, and imipramine and the antipsychotics haloperidol and olanzapine showed higher DRC factors than those calculated for adults. The DRC factors of amphetamine and methylphenidate were higher in children (6-12 years) but not in adolescents (13-17 years). On the contrary, the antipsychotic quetiapine and the mood-stabilizing antiepileptics lamotrigine, oxcarbazepine, and topiramate showed lower DRC factors than those calculated for adults. CONCLUSIONS: It was concluded that concentrations of neuroactive/psychoactive drugs to be expected in blood for a given dose may differ between adults and children or adolescents, most probably owing to age-dependent differences in the elimination of these drugs.

Sensitive imprinted optical sensor based on mesoporous structure and green nanoparticles for the detection of methamphetamine in plasma and urine.

Methamphetamine (MA), a psychoactive substance with many medicinal applications in different countries, has destructive impacts on the nervous system and brain and can lead to addiction. The optimal system for MA determination must be able to measure the tiny amount of MA in complex matrixes accurately. In the current work, a simple and biocompatible sensitive optical probe was developed based on molecularly imprinted polymers (MIPs) technique and by using green CQDs and mesoporous structured imprinting microspheres (SiO2@CQDs@ms-MIPs). CQDs (ФF = 33%) were synthesized via the hydrothermal method using natural chewing gum as carbon source. SiO2 nanoparticles were used as the backup substrate for the placement of CQDs. In spite of biocompatibility, porosity and having high specific area are the unique features of SiO2 nanoparticles. When MA is present, the fluorescence response of MIPs enhances. This is caused by the passivation and adjustment of active clusters that are present on the surface of CQDs. By this optical sensor, the favorable linear dynamic range (5.0-250 µM) and the detection limit (1.6 µM) were obtained. The applicability of the advanced sensor was studied in real samples such as human urine and human blood plasma. Acceptable results were obtained and recovery amounts were in the 92-110% interval.

An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Intoxicated aggression: Do alcohol and stimulants cause dose-related aggression? A review.

RATIONALE: Violence and drug use are significant public health challenges that are strongly linked. It is known that alcohol plays a major role in the causation of unnatural deaths and that stimulants like cocaine and amphetamine are often implicated in aggressive acts or violence. However, a clear causal relationship between these substances and aggression, and more specifically a blood concentration threshold at which intoxicated aggression emerges is lacking. In case of a crime and subsequent law enforcement, knowledge about dose-response relationships could be of pivotal importance when evaluating the role of alcohol and drugs in aggressive offences. AIMS: The present review aimed to determine whether there is a causal relation between intoxication with these psychoactive substances and aggression, and to define blood concentration thresholds above which these substances elicit aggression. METHODS: Empirical articles published between 2013 and 2017 and review papers containing the predefined search strings were identified through searches in the PubMed and Embase databases and additional reference list searches. The complete search query yielded 1578 publications. Initially all articles were manually screened by title and abstract. Articles with irrelevant titles, given the selected search terms and review aims were discarded. Remaining articles were carefully studied and those that did not comply with the main objectives of this review were discarded. At the end of this process, 167 titles were found eligible for review. FINDINGS AND CONCLUSION: While placebo-controlled experimental studies clearly showed a causal link between alcohol and aggression, it is evident that such a link has not yet been established for cocaine and amphetamines. In case of alcohol, it is clear that there are various individual and contextual factors that may contribute to the occurrence of an aggressive act during intoxication. A clear threshold blood alcohol concentration has not been defined yet for alcohol, but a statistically significant increase of aggression has been demonstrated at a dose of 0.75 g/kg and higher. Future studies into intoxicated aggression should include multiple doses of alcohol and stimulants and take into account individual and contextual factors.

Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.