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.

Methamphetamine-associated pulseless electrical activity in a young child.

This is a case report of a 19-month-old female who presented to the emergency department in cardiac arrest after methamphetamine exposure. Prior to presentation, she had seizure-like activity and then became unresponsive. On arrival, she had dilated pupils, intermittent clonus, and pulseless electrical activity. She was found to have full thickness circumferential burns of her bilateral lower extremities. She received 12 doses of epinephrine, cardiopulmonary resuscitation, and volume resuscitation after which she had return of spontaneous circulation and was transferred to the intensive care unit on an epinephrine drip. Initial laboratory studies showed a mixed metabolic and respiratory acidosis and hyperglycemia. An initial urine immunoassay for drugs of abuse was negative, however, 5 h later, a second urine immunoassay was positive for amphetamine. The first specimen was also sent for liquid chromatography-mass spectrometry analysis that later returned positive for methamphetamine and amphetamine. In retrospect, the initial urine screen was found to have evidence of amphetamine below the threshold for positivity (500 ng/mL), and the second urine specimen was highly positive, with an amphetamine level of >1450 ng/mL. In this case, what turned out to be a sub-threshold rather than undetectable level was clinically significant, highlighting the challenges of urine screening in cases of suspected poisoning syndromes with atypical presentations. Our case also suggests the possibility of PEA as a presentation of methamphetamine toxicity in a child.

Screening for Opioid and Stimulant Exposure In Utero Through Targeted and Untargeted Metabolomics Analysis of Umbilical Cords.

BACKGROUND: Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs. METHODS: A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography-mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography-mass spectrometry instrument for positive confirmation and quantitative analysis. RESULTS: Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl. CONCLUSIONS: Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.

Use of Amphetamine-Type Stimulants Among Emergency Department Patients With Untreated Opioid Use Disorder.

STUDY OBJECTIVE: Concurrent use of amphetamine-type stimulants among individuals with opioid use disorder can exacerbate social and medical harms, including overdose risk. The study evaluated rates of amphetamine-type stimulant use among patients with untreated opioid use disorder presenting at emergency departments in Baltimore, MD; New York, NY; Cincinnati, OH; and Seattle, WA. METHODS: Emergency department (ED) patients with untreated opioid use disorder (N=396) and enrolled between February 2017 and January 2019 in a multisite hybrid type III implementation science study were evaluated for concurrent amphetamine-type stimulant use. Individuals with urine tests positive for methamphetamine, amphetamine, or both were compared with amphetamine-type stimulant-negative patients. RESULTS: Overall, 38% of patients (150/396) were amphetamine-type stimulant positive; none reported receiving prescribed amphetamine or methamphetamine medications. Amphetamine-type stimulant-positive versus -negative patients were younger: mean age was 36 years (SD 10 years) versus 40 years (SD 12 years), 69% (104/150) versus 46% (114/246) were white, 65% (98/150) versus 54% (132/246) were unemployed, 67% (101/150) versus 49 (121/246) had unstable housing, 47% (71/150) versus 25% (61/245) reported an incarceration during 1 year before study admission, 60% (77/128) versus 45% (87/195) were hepatitis C positive, 79% (118/150) versus 47% (115/245) reported drug injection during 1 month before the study admission, and 42% (62/149) versus 29% (70/244) presented to the ED for an injury. Lower proportions of amphetamine-type stimulant-positive patients had cocaine-positive urine test results (33% [50/150] versus 52% [129/246]) and reported seeking treatment for substance use problems as a reason for their ED visit (10% [14/148] versus 19% [46/246]). All comparisons were statistically significant at P<.05 with the false discovery rate correction. CONCLUSION: Amphetamine-type stimulant use among ED patients with untreated opioid use disorder was associated with distinct sociodemographic, social, and health factors. Improved ED-based screening, intervention, and referral protocols for patients with opioid use disorder and amphetamine-type stimulant use are needed.

Analysis of hydroxylated phenylalkylamine stimulants in urine by GC-APPI-HRMS.

A gas chromatography-atmospheric pressure photoionization-high-resolution mass spectrometry (GC-APPI-HRMS) method was developed for the determination of eight phenylalkylamine stimulants in urine samples. Spiked urine samples were hydrolyzed, processed by solid-phase extraction, and derivatized before analysis. Two derivatization reactions were studied: the formation of trimethylsilyl (TMS) derivatives with N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) and trimethylsilyl/trifluoroacetyl (TMS/TFA) derivatives with MSTFA and N-methyl-bis (trifluoroacetamide) (MBTFA) as derivatization reagents. Gas chromatography of both derivatives was performed with a 100% dimethylsiloxane column and a good separation of all isomeric compounds was achieved. To maximize the signal of the protonated molecule [M+H]+, the APPI most critical parameters were optimized. Three solvents were tested as dopant agents, with acetone yielding the lower in-source collision-induced dissociation (CID) fragmentation. The acquisition was performed in full scan and product ion scan (parallel reaction monitoring, PRM) using a quadrupole-Orbitrap mass analyzer (35,000 FWHM at m/z 200) in positive ion detection mode. At the optimal working conditions, the full scan method was evaluated for the fulfillment of identification requirements in doping analysis. Selectivity, limits of detection, matrix effect, and precision were estimated to validate the method for confirmation purposes and its applicability was tested by the analysis of spiked samples as well as by the analysis of samples obtained after the administration of some of the compounds to healthy volunteers. Results were compared with those obtained by GC-electron ionization-MS, demonstrating that the GC-APPI-HRMS method improved selectivity and sensibility, achieving lower limits of detection and satisfactory reproducibility.

Methamphetamine intoxication and acute kidney injury: A prospective observational case series.

AIM: The effects of methamphetamine intoxication on the kidney are not well reported. We aimed to investigate acute kidney injury (AKI) associated with methamphetamine intoxication, in particular its severity, duration and association with rhabdomyolysis. METHODS: This is a prospective observational series of methamphetamine-intoxicated patients presenting to an Emergency Department. Patients self-reporting recent methamphetamine use, with a positive urine drug screen and an elevated creatinine, were eligible for the study. Urinary neutrophil gelatinase-associated lipocalin (NGAL) was measured, and serum creatinine, creatine kinase and cystatin C concentrations were performed on arrival and at several time points until discharge from hospital. Demographic and clinical data were obtained from the medical records. RESULTS: There were 634 presentations with methamphetamine intoxication over a 10-month period, with 73/595(12%) cases having an elevated serum creatinine concentration on arrival. Fifty presentations in 48 patients were included in the study. Most patients (85%) were male with a median age of 32 years. The median serum creatinine concentration on presentation was 125 µmol/L (IQR:113-135 µmol/L) with 45 (90%) presentations meeting diagnostic criteria for AKI. Concurrent rhabdomyolysis occurred in 22 (44%) presentations with a median CK of 2695 U/L (IQR:1598-5060 U/L). Cystatin C was elevated (> 0.98 mg/L) in 18 cases. An elevated NGAL concentration (>150 µg/L) was present in five (10%) cases. No patients required dialysis. The median length of stay was 19 hours (IQR 14-24 hours). CONCLUSION: AKI is common in methamphetamine intoxication. The kidney injury is relatively mild and short-lived, resolving with crystalloid therapy.

A complicated case of bowel obstruction with sepsis and methamphetamine toxicity in a child with pica.

In this report, a pediatric case of bowel obstruction with sepsis complicated by methamphetamine toxicity is described. The decedent, an eleven-year-old female with a clinical history of pica, was found unresponsive in her home and pronounced dead following unsuccessful resuscitative efforts. Radiologic imaging showed multiple radio-opaque foreign objects in the stomach and bowel. Autopsy revealed a green leafy substance, coins and other metallic items, folded paper, and plastic in her stomach and bowels. Postmortem iliac blood and urine tested positive for amphetamine and methamphetamine. While the decedent's medical history and autopsy findings provided evidence consistent with bowel obstruction with sepsis due to the ingestion of foreign materials, the high methamphetamine concentration was suggestive of concurrent methamphetamine toxicity. Unique complications associated with this case include the phenomenon that methamphetamine toxicity and bowel obstruction can present similarly in children and the reported opinion that accidental drug ingestion is uncommon in children over the age of five. This case emphasizes that the age range for suspected accidental drug ingestion should be expanded for those with pica, as these patients, despite being older, may not be able to differentiate between what they should and should not ingest. Furthermore, when treating a pediatric patient with pica that appears to present with bowel obstruction, unintentional drug ingestion should also be considered, particularly if there is a suspicion that the child lives in a household where drugs are abused, given the prospect that drug toxicity can present similarly.

Correlates of Validity of Self-Reported Methamphetamine Use among a Sample of Dependent Adults.

BACKGROUND: Self-reported data are widely used in substance-use research, yet few studies have assessed the validity of self-reported methamphetamine use compared to biological assays. OBJECTIVES: We sought to assess the validity and correlates of validity of self-reported methamphetamine use compared to urine toxicology (UTOX). METHODS: Using a sample of methamphetamine-dependent individuals enrolled in a randomized controlled pharmacotherapy trial in the United States (n = 327 visits among 90 participants), we calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the kappa coefficient of self-reported methamphetamine use in the past 3 days compared to UTOX, as well as the NPV of self-reported methamphetamine use over an extended recall period of 1 month. We used multivariable logistic regression models to assess correlates of concordance between self-reported methamphetamine use and UTOX. RESULTS: The sensitivity of self-reported methamphetamine use in the past 3 days was 86.7% (95% confidence intervals (95%CI): 81.4%-91.4%), the specificity was 85.3% (77.7-91.3), the PPV was 91.5% (86.9-94.8), and the NPV was 78.0% (69.4-86.1), compared to UTOX (kappa = 0.71). The NPV over the extended recall period was 70.6% (48.0-85.7). In multivariable analyses, validity of self-reported methamphetamine use was higher for older participants but lower during follow-up compared to baseline and when polysubstance use or depressive symptoms were reported. Conclusions/Importance: Our sample of methamphetamine-dependent adults reported recent methamphetamine use with high validity compared to UTOX. Validity increased with age but decreased when participants reported depressive symptoms or polysubstance use as well as later in the study timeline and during longer recall periods.

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

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

Pharmacokinetics study of mazindol in plasma, oral fluid, and urine of volunteers.

PURPOSE: There are no pharmacokinetics studies in oral fluid reported in the literature, as well as there are no data on correlation of drug levels in plasma, urine, and oral fluid in order to propose alternative matrices to monitor the use of mazindol by drivers. The present work aimed to study, preliminarily, mazindol's pharmacokinetics in plasma and oral fluid, as well as investigate the correlation of drug levels in urine, plasma, and oral fluid. METHOD: Blood, urine, and oral fluid samples from seven healthy male volunteers were collected at 0, 1, 2, 4, 5, 6, 8, 10, and 24 h after administration of tablets of 2 mg mazindol and analyzed by a previously validated method by LC-MS with liquid-liquid extraction. Levels of the drug found were higher in plasma when compared with oral fluid and higher in urine in relation to plasma. The study of the mazindol's pharmacokinetics showed that the most suitable model to describe the variation of the concentration over time is the compartment open model with absorption and elimination following the first-order kinetics, and confirming literature data, drug is metabolized, being the major metabolite detected, but not quantified. CONCLUSION: It was not found a good correlation between the concentrations of mazindol in urine and plasma, but between plasma and oral fluid, there was a good correlation, suggesting this as an alternative matrix to plasma. However, studies involving more subjects are needed.

"Dilute-and-inject" multi-target screening assay for highly polar doping agents using hydrophilic interaction liquid chromatography high resolution/high accuracy mass spectrometry for sports drug testing.

In the field of LC-MS, reversed phase liquid chromatography is the predominant method of choice for the separation of prohibited substances from various classes in sports drug testing. However, highly polar and charged compounds still represent a challenging task in liquid chromatography due to their difficult chromatographic behavior using reversed phase materials. A very promising approach for the separation of hydrophilic compounds is hydrophilic interaction liquid chromatography (HILIC). Despite its great potential and versatile advantages for the separation of highly polar compounds, HILIC is up to now not very common in doping analysis, although most manufacturers offer a variety of HILIC columns in their portfolio. In this study, a novel multi-target approach based on HILIC high resolution/high accuracy mass spectrometry is presented to screen for various polar stimulants, stimulant sulfo-conjugates, glycerol, AICAR, ethyl glucuronide, morphine-3-glucuronide, and myo-inositol trispyrophosphate after direct injection of diluted urine specimens. The usage of an effective online sample cleanup and a zwitterionic HILIC analytical column in combination with a new generation Hybrid Quadrupol-Orbitrap® mass spectrometer enabled the detection of highly polar analytes without any time-consuming hydrolysis or further purification steps, far below the required detection limits. The methodology was fully validated for qualitative and quantitative (AICAR, glycerol) purposes considering the parameters specificity; robustness (rRT < 2.0%); linearity (R > 0.99); intra- and inter-day precision at low, medium, and high concentration levels (CV < 20%); limit of detection (stimulants and stimulant sulfo-conjugates < 10 ng/mL; norfenefrine; octopamine < 30 ng/mL; AICAR < 10 ng/mL; glycerol 100 µg/mL; ETG < 100 ng/mL); accuracy (AICAR 103.8-105.5%, glycerol 85.1-98.3% at three concentration levels) and ion suppression/enhancement effects.

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.

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.

A randomized placebo controlled trial demonstrates the effect of dl-methylephedrine on brain functions is weaker than that of pseudoephedrine.

Intellectual drug doping in athletics by using stimulants that affect central nervous system functions has been diversified. Stimulants are regulated by the World Anti-Doping Agency according to their levels of urinary concentration. Positron emission tomography could evaluate how stimulants affect central nervous system functions. We aimed to evaluate the effect of stimulants on brain function by examining the difference in brain dopamine transporter occupancy by PET after administration of dl-methylephedrine or pseudoephedrine at the clinical maximum daily dose. Four PET scans without and with drug administration (placebo, dl-methylephedrine 150 mg and pseudoephedrine 240 mg) were performed. The concentrations of dl-methylephedrine and pseudoephedrine in plasma and urine were measured. DAT occupancies in the striatum with placebo, dl-methylephedrine and pseudoephedrine were calculated by PET images. The urinary concentration of dl-methylephedrine (12.7 µg/mL) exceeded the prohibited concentration (10 µg/mL), but the DAT occupancy with dl-methylephedrine (6.1%) did not differ (p = 0.92) from that with placebo (6.2%). By contrast, although the urinary concentration of pseudoephedrine (144.8 µg/mL) was below the prohibited concentration (150 µg/mL), DAT occupancy with pseudoephedrine was 18.4%, which was higher than that with placebo (p = 0.009). At the maximum clinical dose, dl-methylephedrine was shown to have weaker effects on brain function than pseudoephedrine.

Methamphetamine as the most common concomitant substance used with pregabalin misuse.

BACKGROUND AND AIM: Non-medical use of Pregabalin (PGB) is a growing concern in many countries because of the serious consequences associated with their abuse. Judicial cases within the probation system, multiple drug users, and patients in treatment programs administered PGB at higher doses than suggested, commonly without prescription. For this reason, it is important to analyze PGB by adding it to the routine analysis scale in determining whether PGB is used for medical purposes or abuse. In this study, PGB analyzed (single or multiple substance use, concomitant substances) in urine samples of forensic and clinical cases by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition to the sociodemographic and clinical characteristics of pregabalin-positive cases, the results were evaluated separately from a clinical and forensic perspective. METHODS: All urine samples which was admitted to Addiction Toxicology Laboratory from 'drug abuse probation system' (forensic cases, n = 640) and from various departments of our hospital (clinical cases, n = 371) between December 2022 and April 2023. Screening analysis were carried out by immunoassay in total 1011 cases. LC-MS/MS method simultaneously analyzed amphetamine, benzoilecgonine, cocaine, codeine, metamphetamine, morphine, 3,4-metilenedioksi-N-metilamfetamin (MDMA), 11-nor-9-karboksi-Δ9-tetrahidrokannabinol and pregabalin in urine samples. PGB was added to the our routine substance screening analysis scale in December 2022 to detect pregabalin use. RESULTS: PGB was detected in 12.3% of probabition cases and 13.2% of clinical cases. The mean age of PGB positive cases was 26.55 ± 7,52 years old, predominantly males (%85,9). Single PGB was detected in 53.2% of forensic cases (n = 42), and 38.7% of clinical cases (n = 19). The most common substance detected concomitantly with PGB was amphetamine type stimulants (ATSs:amphetamine, methamphetamine, ecstasy/MDMA etc.) (22.8% of forensic cases and 46.9% of clinical cases), followed by concomitant cannabis use (24.1% of forensic cases and 26.5% of clinical cases). Concomitant opioid use was rare (1.3% of forensic cases and 4.1% of clinical cases). Detection of PGB was significantly different across months on which the samples were collected (x2 = 82.8, df=4, p < 0.001). CONCLUSION: Inconsistently with previous studies suggesting opioids as the most prevalant substances concominant with PGB, our results showed that stimulants (especially ATSs) were the most prevelant substances concominant with PGB, followed by cannabis. High proportion of PGB detection in probabition cases, frequently as a single substance abuse takes attention. These results suggest that PGB, may be used to avoid legal consequences. It is important for laboratories to be aware that they need to make changes as addition of newly abused substances in their analysis panels, when necessary, as differences between regions and cultures affect substance use patterns.

Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients.

OBJECTIVE: We conducted a pharmacokinetic (PK) study and a pharmacodynamic (PD) study to assess whether Roux-en-Y gastric bypass (RYGB) surgery is associated with significant changes to PK and PD of oral medications. BACKGROUND: The effect of RYGB on oral drug disposition is not well understood. METHODS: An oral cocktail of probe drugs for major drug-metabolizing enzymes (caffeine, tolbutamide, omeprazole, dextromethorphan, and oral and intravenous midazolam) was administered to 18 RYGB recipients and 18 controls. Timed blood and urine samples were obtained for PK analyses. Forty mg of oral furosemide was administered to 13 RYGB recipients and 14 controls, and urine and blood samples were collected for assessing furosemidePK, and urine volume and urine sodium excretion for PD analyses. RESULTS: Compared with controls, the RYGB group had significantly lower time to maximum plasma concentration (tmax) for caffeine (0.58 ± 0.5 vs 2.1 ± 2.2 hours, P < 0.0001), tolbutamide (1.4 ± 1.8 vs 2.1 ± 2.2 hours, P = 0.0001), omeprazole (1.1 ± 1.1 vs 4.4 ± 1.3 hours, P < 0.0001), and oral midazolam (0.5 ± 0.2 vs 0.7 ± 0.4 hours, P < 0.01). However, maximum plasma concentration, half-life, area under the curve, and oral bioavailability were not different. Compared with controls, the RYGB group had brisk natriuresis, with significantly lower tmax for urine sodium (1.3 ± 0.5 vs 3.1 ± 2.3 hours, P < 0.02) and correspondingly lower tmax for furosemide (1.8 ± 0.3 vs 4.2 ± 1.2 hours, P = 0.006). However, 6-hour urine sodium and 6-hour urine volume were not different between the two groups. CONCLUSIONS: RYGB recipients have significantly shorter tmax for the studied orally administered medications, but otherwise no other significant changes in PK were reported.

Sudden cardiac death associated with methylone use.

The rise in popularity of "bath salts" as safe alternatives to MDMA (3,4-methylenedioxymethamphetamine), methamphetamine, and other illicit substances has resulted in increased scrutiny of the contents and toxicology associated with these products. We report a case of sudden death related to the synthetic cathinone methylone (3,4-methylenedioxy-N-methylcathinonmethylone) in a previously healthy 19-year-old man. Although several fatal case reports have been published involving methylone and other synthetic cathinones, this is the first reported case of sudden cardiac death associated with methylone use. Although lack of published data prevented a comparison of blood methylone concentrations between our case and existing reports, the amount of methylone we detected postmortem (0.07 mg/dL) is below those reported in MDMA-related fatalities. Our report suggests that methylone toxicity has been greatly underestimated by users of this synthetic cathinone.

Enantiomeric separation of some common controlled stimulants by capillary electrophoresis with contactless conductivity detection.

CE methods with capacitively coupled contactless conductivity detection (C(4)D) were developed for the enantiomeric separation of the following stimulants: amphetamine (AP), methamphetamine (MA), ephedrine (EP), pseudoephedrine (PE), norephedrine (NE) and norpseudoephedrine (NPE). Acetic acid (pH 2.5 and 2.8) was found to be the optimal background electrolyte for the CE-C(4)D system. The chiral selectors, carboxymethyl-ß-cyclodextrin (CMBCD), heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DMBCD) and chiral crown ether (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18C6H(4)), were investigated for their enantioseparation properties in the BGE. The use of either a single or a combination of two chiral selectors was chosen to obtain optimal condition of enantiomeric selectivity. Enantiomeric separation of AP and MA was achieved using the single chiral selector CMBCD and (hydroxypropyl)methyl cellulose (HPMC) as the modifier. A combination of the two chiral selectors, CMBCD and DMBCD and HPMC as the modifier, was required for enantiomeric separation of EP and PE. In addition, a combination of DMBCD and 18C6H(4) was successfully applied for the enantiomeric separation of NE and NPE. The detection limits of the enantiomers were found to be in the range of 2.3-5.7 µmol/L. Good precisions of migration time and peak area were obtained. The developed CE-C(4)D method was successfully applied to urine samples of athletes for the identification of enantiomers of the detected stimulants.

Excretion of mephedrone and its phase I metabolites in urine after a controlled intranasal administration to healthy human volunteers.

Mephedrone is a stimulant drug structurally related to cathinone. At present, there are no data available on the excretion profile of mephedrone and its metabolites in urine after controlled intranasal administration to human volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Urine was collected at different timepoints on Day 1 and then on Days 2, 3 and 30. Samples were analysed for the presence of mephedrone and its metabolites, namely, dihydro-mephedrone, nor-mephedrone (NOR), hydroxytolyl-mephedrone, 4-carboxy-mephedrone (4-carboxy) and dihydro-nor-mephedrone (DHNM), by a validated liquid chromatography-tandem mass spectrometry method. All analytes were detected in urine, where 4-carboxy (Cmax = 29.8 µg/ml) was the most abundant metabolite followed by NOR (Cmax = 377 ng/ml). DHNM was found at the lowest concentrations (Cmax = 93.1 ng/ml). Analytes exhibited a wide range of detection windows, but only 4-carboxy and DHNM were detectable in all samples on Day 3, extending the detection time of mephedrone use. Moreover, mephedrone had a mean renal clearance of 108 ± 140 ml/min, and 1.3 ± 1.7% of unchanged parent drug was recovered in urine in the first 6 h post administration. It is hoped that this novel information will be useful in future studies involving mephedrone and other stimulant drugs.

Tourette syndrome and excitatory substances: is there a connection?

BACKGROUND AND PURPOSE: The objective of this study is to investigate the relationship between excitatory substances by testing the urine in children with Tourette syndrome (TS). METHODS: We performed a control study involving 44 patients with TS and 44 normal children by investigating the children's daily eating habits. We used the gas chromatograph-mass spectrometer and liquid chromatograph-mass spectrometer from Agilent. Substances for detection included 197 excitatory substances prohibited by the International Olympic Committee and other substances with similar chemical structures or biological functions for urine samples. RESULTS: Forty-four patients who did not take any drugs in the past 2 weeks enrolled in the study. The positive rate in the experiment group was three cases, while it was negative in the control group. The level of 1-testosterone increased in one extremely severe TS patient who ate large amounts of puffed food and drank an average of 350 ml of cola per day. Cathine and other substances with similar chemical constitution or similar biological effects increased in one severe TS patient who ate bags of instant noodles daily, according to the high score of the Yale Global Tic Severity Scale. CONCLUSION: An increase in ephedrine type, testosterone, and stimulants may be related to the pathogenesis of TS. Unhealthy food possibly causes TS. The relationship between excitatory substances and TS needs to be explored with the goal of providing more information on diagnosing and treating TS.