Toxicological Screening Research Articles

The Impact of Chronic Cannabis Use on Esophageal Motility in Patients Referred for Esophageal Manometry.

Tetrahydrocannabinol, the main psychoactive compound in cannabis, binds with high affinity to the cannabinoid 1 receptor. Small randomized controlled studies using conventional manometry have shown that the cannabinoid 1 receptor can modulate esophageal function, namely transient lower esophageal sphincter relaxation frequency and lower esophageal sphincter tone. The effect of cannabinoids on esophageal motility in patients referred for esophageal manometry has not been fully elucidated using high-resolution esophageal manometry (HREM). We aimed to characterize the clinical effect of chronic cannabis use on esophageal motility utilizing HREM. Patients who underwent HREM from 2009 to 2019 were identified at 4 academic medical centers. The study group consisted of patients with a noted history of chronic cannabis use, a diagnosis of cannabis-related disorder, or a positive urine toxicology screen. Age and gender-matched patients with no history of cannabis use were selected to form the control group. Data on HREM metrics based on the Chicago classification V3, and the prevalence of esophageal motility disorders were compared. Confounding effects of BMI and medications on esophageal motility were adjusted for. Chronic cannabis use was found to be an independent negative predictor of weak swallows (β=-8.02, P =0.0109), but not a predictor of failed swallows ( P =0.6890). The prevalence of ineffective esophageal motility was significantly lower in chronic cannabis users compared with nonusers (OR=0.44, 95% CI 0.19-0.93, P =0.0384). There was no significant difference in the prevalence of other esophageal motility disorders between the 2 cohorts. In patients with dysphagia as their primary indication for HREM, chronic cannabis use was found to be independently associated with increased median integrated relaxation pressure (β=6.638, P =0.0153) and increased mean lower esophageal sphincter resting pressure (β=10.38, P =0.0084). Chronic cannabis use is associated with decreased weak swallows and reduced prevalence of ineffective esophageal motility in patients referred for esophageal manometry. In patients referred for dysphagia, chronic cannabis use is associated with increased integrated relaxation pressure and lower esophageal sphincter resting pressure, though not to levels above the normal range.

Assessment of pheniramine in alternative biological matrices by liquid chromatography tandem mass spectrometry.

Pheniramine is an over-the-counter antihistamine drug. Its accessibility and low cost made it more popular among drug abusers in Pakistan. In this study, pheniramine was quantified in both conventional and alternative specimens of twenty chronic drug abusers, aged 16-50years, who were positive for pheniramine in comprehensive toxicological screening for drugs by gas chromatography with mass spectral detection in positive electron impact mode. Pheniramine was extracted from biological specimens using solid phase extraction and liquid chromatography tandem mass spectrometry was employed for quantification. Chromatographic separation was carried out on a Poroshell120EC-18 (2.1mm × 50mm × 2.7µm) column using water-acetonitrile in formic acid (0.1%) mobile phase in gradient elution mode with 500μL/min flow rate. Positive electrospray ionization mode and multi-reaction monitoring with ion transitionsm/z241.3 → 195.8 and 167.1 for pheniramine andm/zm/z247.6 → 173.1 for pheniramine-d6 were employed. The quantification method showed good linear ranges of 2-1000ng/mL in blood, urine, and oral fluid; 2-1000ng/mg in hair and 5-1000ng/mg in nail with ≥ 0.985% coefficient of linearity. The retention time of pheniramine was 3.0 ± 0.1min. The detection and lower quantification limits were 1ng/mL and 2ng/mL for blood, urine, oral fluid and hair whereas 2.5ng/mg and 5ng/mg for nail, respectively. Mean extraction recovery and ionization suppression ranged 86.3-95.1% and -4.6 to -14.4% in the studied matrices. Intra-day and inter-day precision were 4.1-9.3% and 2.8-11.2%, respectively. Pheniramine levels in specimens of drug abusers were 23-480ng/mL in blood, 72-735ng/mL in urine, 25-379ng/mL in oral fluid, 10-170ng/mg in hair and 8-86ng/mg in nail specimens. Alternative specimens are of utmost significance in clinical and medico-legal cases. In this study, authors compared matrix-matched calibration curves to blood calibration curve and obtained results within ± 10%; thereby justifying the use of blood calibration curve for urine, oral fluid, hair, and nail specimens.

Opioid abuse, the escalating crisis, xylazine co-use, and the forensic toxicology challenges

Introduction: The opioid crisis represents a longstanding public health emergency, significantly worsened by the concurrent use of xylazine. This epidemic has led to a surge in opioid-related fatalities, marking it as a pressing health crisis with global implications. The combination of xylazine with fentanyl and its analogs significantly increases the risk of overdose deaths. This study aims to analyze the current situation by reviewing scientific and governmental publications on the topic. Methods: Our analysis, established on data from PubMed, Google Scholar, and Scopus, highlights the pharmacological risks related to the combination of xylazine and synthetic opioids, such as fentanyl. It underlines the increased chances of fatal overdoses due to this combination. Results: The research associates weaknesses in current forensic toxicology screenings that fail to effectively detect these dangerous compounds. The illegal synthesis of these substances is a key challenge in directing the emergency. The combination of xylazine with synthetic opioids shows a significant public health risk, worsening the already critical opioid crisis. There is a critical need for improved drug detection and analysis methods to combat this growing challenge. Conclusion: Developing forensic toxicology screenings to precisely identify the presence of these substances is crucial for both the diagnosis and prevention of fatal overdoses. Our findings emphasize the requirement for immediate and concerted efforts to address the complexities of the opioid epidemic and highlight the potential consequences of public health strategies intended to mitigate this crisis.

Abstract 4701: A novel microtubule disruptor exerts broad anticancer efficacy with a tolerable safety profile

Abstract Initial evaluation of the prenylated hydroxy-stilbene isolated from bee propolis, AUS_001, in the NCI 60 human cell line anticancer screen showed significant growth inhibitory effects with the most robust being observed in leukemia, central nervous system and breast cancer cell lines. The aim of the current study was to further assess the potency of AUS_001 in vitro and investigate its safety profile and mechanism of action. A commercially available cell-based profiling screen (OncoPanel®) identified significant AUS_001-induced growth inhibition in 273 out of 280 cancer cell lines with a concentration causing 50% cell growth inhibition in the range of 0.021-0.94 µM, while non-neoplastic cells required an average of 20x higher concentration to generate similar efficacy. These findings indicate that AUS_001 exerts a high degree of potency across 30 cancer types with a selectivity for cancer versus normal cells. Maximum tolerated dose studies in mice illustrated that orally administered AUS_001 is well tolerated at doses 4 times greater than those that conferred antitumor efficacy, with no myelosuppression or other overt toxicities observed. Predictive toxicology and safety screening indicated that AUS_001 exerts a strong safety profile as evidenced by absence of mutagenic potential in the Ames test using up to 100 µM drug doses and low hERG-blocking liability with a half-maximal inhibitory concentration of 65 µM. Notably, AUS_001 is a poor substrate of the drug efflux transporter, P-glycoprotein 1 (Pgp), as it does not inhibit drug-stimulated Pgp ATPase activity and retains efficacy in high Pgp-expressing models in vitro. Subsequently, the effects of AUS_001 were explored in the ToxTracker® assay, consisting of a panel of mammalian stem cell lines that contain fluorescent reporters for the exploration of DNA damage, oxidative stress, and protein damage using flow cytometry. Robust activation of the Rtkn genotoxicity reporter under low cytotoxicity conditions, in combination with accumulation of cells in G2/M phases of the cell cycle within 4 h and an increase in aneuploid cells after 24 h of drug treatment, suggested an aneugenic mode of action, typically caused by tubulin-targeting agents or mitotic kinase inhibitors. Biochemical tubulin polymerization assays then revealed that AUS_001 acts as a direct tubulin destabilizing agent and monitoring microtubule dynamics in GFP-tubulin reporter cells provided evidence that AUS_001 blocks microtubule assembly. Our studies have elaborated the mechanism of AUS_001 as an inhibitor of tubulin polymerization. The favorable safety profile of AUS_001, along with its ability to circumvent Pgp-mediated multidrug resistance, provides potential for efficacy against multiple cancers where microtubule destabilization is proven to be an effective target. Citation Format: Herman Lelie, Inger Brandsma, Giel Hendriks, Lee R. Cavedine, Brogan A. Epkins, Steven M. Garner, Andrew J. Cook, Muthukrishnan Renganathan, Yong Zhao, Alastair J. King, Peter Y.W. Chan, April Risinger, Marina Koutsioumpa. A novel microtubule disruptor exerts broad anticancer efficacy with a tolerable safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4701.

Human red blood cell acetylcholinesterase activity: a revisit after fifteen years

Human red blood cell acetylcholinesterase (RBC-AChE) activity is valuable for detecting potential exposure to cholinesterase inhibiting substances (CIS). A reliable population-based RBC-AChE activity reference range is critical for early and massive clinical and occupational toxicology screening. Previous published studies were often limited to small numbers of subjects, various testing methods, and crude statistical data analyses. We tested 4818 adult subjects with a well-established 17-minute modified Michel method over a 2-year period. We conducted a retrospective data analysis and systematically investigated on the influences to testing values from gender, age, age group, and their combinations and interactions. No significant difference was observed in the testing values between males (mean, medium, interquartile range = 0.76, 0.76, 0.71–0.80 ΔpH/h, respectively) and females (mean, medium, interquartile range = 0.76, 0.76, 0.71–0.81 ΔpH/hour, respectively), when gender was the only factor considered (p = 0.7238). However, with age progression, male testing values exhibited a consistent upward trend, while females did not show any clear patterns. Linear regression analysis of the data revealed that gender, age, and age group more or less affected testing values either as independent variables or with their combinations and interactions. However, more potential factors need to be included to achieve better testing value predictions. We recommend the toxicological testing community to adopt a new set of age group specific RBC-AChE activity reference ranges for males (0.68–0.80, 0.69–0.81, 0.70–0.83, 0.71–0.84, and 0.73–0.87 ΔpH/h for 18–29, 30–39, 40–49, 50–59, and ≥60 years old, respectively) while keeping the current reference range (0.63–0.89 ΔpH/hour) for females.

Coupling thin layer chromatography with mass spectrometry for detection and identification of sertraline and its metabolite in the urine

The aim of the study was to detect sertraline and its metabolites in urine under standardized thin layer chromatography (TLC) screening conditions and identify the metabolites using the mass spectrometry method. Materials and methods. Urine samples, collected within 30 hours in portions of 20–50 mL, commenced from the seventh hour after the administration of a single therapeutic dose of the drug. The sample preparation process involved dilute acid hydrolysis, followed by the extraction of the native compound and metabolites with chloroform at a pH of 8–9. Thin layer chromatography studies of the extracts were conducted using four unified TLC systems recommended by The International Association of Forensic Toxicologists for general drug screening. Chromatograms were subjected to color reactions with a variety of chromogenic reagents. For the analysis of eluates from chromatograms, a Varian 1200 L mass spectrometer (Netherlands) equipped with a dual quadrupole mass analyzer was employed. Identification was performed through direct sample introduction into the ion chamber, electron-impact ionization (70 eV), and full ion scanning mode. Results. The spot of the native drug on the chromatogram was identified by the Rf, value. Metabolite of sertraline was identified as N-desmethyltrihydroxysertraline by the molecular ion peak in the mass spectrum. Conclusions. The study demonstrated the ability of TLC to detect sertraline and its metabolite, N-desmethyltrihydroxysertraline, in urine after the administration of a single therapeutic dose of the drug. The chromatographic mobility of the native compound and N-desmethyltrihydroxysertraline in the unified TLC screening systems, along with the results of their visualization using chromogenic reagents for toxicological drug screening, was determined. Furthermore, the potential of coupling TLC with mass spectrometry for the separation, detection, and confirmatory identification of sertraline and its metabolic products in urine was established.

Relation of Serum Level of Tramadol With Consumption Dose and Time

Background: This study aimed to find out the relationship between the serum level of tramadol and consumption dose and the time interval between the drug consumption and arrival at the emergency department (ED). Methods: This was a prospective cross-sectional study that included all patients who came to the ED of Sina hospital, a poisoning center, due to the consumption or abuse of tramadol within 6 months. Among these patients, those with unreliable history and history of drug use, those whose primary toxicologic screening in the ED indicated opioids and buprenorphine, and those who used tramadol chronically due to underlying disease were excluded from the study. Demographic characteristics of the patients, the type of consumed drug, the reason for use, the type of complication, and the outcome of the patient extracted from the documentation, blood samples obtained from the patients after obtaining informed consent, and the serum level of tramadol were checked and recorded using the capillary electrophoresis (CE) device. Results: The study investigated the serum levels of tramadol in 43 male patients presenting to the ED due to tramadol consumption or abuse. The median age was 30 years. All patients were male, and the median dose of utilized tramadol was 2000 mg. The average time from consumption to referral was 6 hours, and 14% of patients experienced seizures after taking the medication. The median serum level of tramadol was 46.12 mmol/dL. Furthermore, quadratic regression analysis revealed no significant relationship between tramadol serum levels with the dose (P=0.233) and the interval (P=0.682) between drug consumption and seeking medical attention. Conclusion: These findings suggested that serum levels of tramadol do not correlate with the administered dose or the time elapsed before seeking medical help.

A295 A CHALLENGING DIAGNOSTIC CASE - SEVERE ACUTE HEPATITIS POTENTIALLY ASSOCIATED WITH COVID-19 IN AN IMMUNOCOMPETENT YOUNG ADULT

Abstract Background Severe hepatitis with liver enzymes in the thousands is usually associated with viral etiologies, toxins, vascular aetiologies, acute gall stones, autoimmune hepatitis, and Wilson disease. Acute hepatitis in the moderate range has been associated with COVID19 infection. Aims A potential case of severe hepatitis with initial ALT of 6863, who tested positive for COVID19. Acetaminophen ingestion confounded the presentation. Methods Case Report Results A 48-year-old woman, with history of Insomnia on Zopiclone, presented to Hospital with a 6-day history of fatigue, malaise, muscle aches and subjective fevers. She had a ten pack-years smoking history, consumed 8 alcoholic beverages weekly, used marijuana infrequently, and denied any herbal or naturopathic supplement usage. She was double vaccinated against COVID19 over a year ago. On the 2nd day of symptoms, she ingested 5 grams of Acetaminophen over a 24-hour period. Subsequently, she continued to use Acetaminophen, but did not exceed a daily dosage of 4 grams. On the 5th day, she presented to clinic and was found to have elevated liver enzymes: ALT 6863, AST 5785, ALP 62, GGT 60, and INR 1.1 with Bilirubin 8. She had nausea and emesis, prompting her to present to the hospital on the 6th day. The patient was alert and oriented, with mild tenderness in the right upper quadrant with no jaundice, ascites, peripheral edema, or encephalopathy. She had reactive lymphocytosis consistent with a potential viral infection. Testing for acute hepatitis A, B, and C, HIV, EBV, CMV, herpes simplex virus, and varicella-zoster was negative. COVID19 was detected by rapid antigen testing and confirmed via PCR. Blood and urine toxicology screens were unremarkable. Acetaminophen was detected at a low level of 67 μg/mL at presentation and given the diagnostic dilemma & concern for concomitant acetaminophen-associated liver injury she was started on N-acetylcysteine (NAC) infusion. Acetaminophen level was trended until undetectable. Ceruloplasmin and alpha-1 antitrypsin were unremarkable. Iron studies showed an elevated Ferritin 1032. Autoimmune workup was negative except for anti-dense fine speckled autoantibodies with 1:80 (low) titre. Abdominal ultrasound with doppler was normal. Her liver enzymes improved (Figure1) without signs of acute fulminant liver failure. She was discharged after 48 hours (day 7). In follow-up, her labs were: ALT 11, AST 16, INR 1.1, Bilirubin 6, and Ferritin 61. Conclusions To our knowledge, this is one of the first case reports of severe hepatitis, possibly due to COVID-19 in an immunocompetent adult, however, concerns for concomitant unintentional acetaminophen toxicity complicate the diagnosis. NAC was given to mitigate diagnostic error given the risk of anchoring bias. If patient condition had deteriorated liver biopsy would have been considered. Funding Agencies None

Occurrence and Prevention of Substance Use Disorder Among Anaesthesiology and Intensive Care Medicine Residents in Indonesia: A Pilot Study

Background: Substance use disorders (SUD) in the population of anaesthesiology and intensive care medicine (ICM) residents have the potential to cause fatal occupational risks. Currently, there are no epidemiological reports regarding the prevalence of SUD among doctors in Indonesia and anaesthesiologists in particular. The purpose of this study was to estimate the occurrence of SUD among anaesthesiology and ICM residents in Indonesia and to recognize the SUD prevention strategy implemented in each teaching hospital. Methods: This was a survey-based observational study using a three-part questionnaire consisting of 20 binary questions, which was pertained to the sociodemographic details, the occurrence and prevention of SUD. Participants were recruited from 16 residency programs with a total of 1 127 active residents registered at the Indonesian College of Anaesthesiology and Intensive Care. All returned surveys were reviewed and scored by hand. The data were compiled and analyzed with numbers and percentages. Results: Returned surveys from 353 residents yielded a 31.3% response rate. Residents from 13 out of 16 registered residency programs in Indonesia participated in this survey. The occurrence of SUD among anaesthesiology and ICM residents in Indonesia was 0.5%. As much as 77.3% of respondents never had toxicological screening. Moreover, 18.2% of respondents were not aware of any routine toxicology screening in their program. Conclusions: The majority of anaesthesiology and ICM residents in Indonesia have risk factors for developing SUD. The need for policies, training, education, and SUD prevention strategies must be immediately addressed.

In silico, anti-inflammatory and acute toxicological evaluation of an indigenous medicinal plant Pterospermum rubiginosum using Sprague-Dawley rats

BackgroundPterospermum rubiginosum has been traditionally used by the tribal inhabitants of Southern India for treating bone fractures and as a local anti-inflammatory agent; however, experimental evidence to support this traditional usage is lacking. The present study aimed to investigate the phytochemical characterization, in silico and in vitro anti-inflammatory evaluation, followed by in vivo toxicological screening of P. rubiginosum methanolic bark extract (PRME).ResultsThe LCMS evaluation revealed the presence of 80 significant peaks; nearly 50 molecules were identified using the LCMS database. In silico analysis showed notable interactions with inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6). In vitro gene expression study supported the docking results with significant down-regulation of iNOS, IL-6, and IL-10. PRME was administered orally to the SD rats and was found to be non-toxic up to 1000 mg/kg body weight for 14 days. The antioxidant enzymes catalase and sodium dismutase exhibited an increased value in PRME-administered groups, possibly due to the diverse phytochemical combinations in bark extract.ConclusionsPRME administration significantly downregulated the gene expression of inflammatory markers, such as iNOS, IL-6, and IL-10. The molecular docking analysis of iNOS and IL-6 supports the in vitro study. In vivo toxicological study of PRME in SD rats was found to be non-toxic up to a concentration of 1000 mg/kg body weight for 14 days.Graphical abstract

Preclinical toxicological assessment of polydatin in zebrafish model

Polydatin (3,4’,5-trihydroxystilbene-3-β-D-glucoside, piceid), a natural stilbenoid found in different plant sources, has gained increasing attention for its potential health benefits. However, prior to its widespread adoption in human therapeutics and consumer products, a comprehensive investigation of its toxicological effects is crucial. In this study, the toxicity of polydatin was investigated in a developmental toxicity test using zebrafish (Danio rerio) as a valuable model for preclinical assessments. We employed the Fish Embryo Test (FET test – OECD n°236) to investigate the effects of polydatin on survival, hatchability, development, and behavior of zebrafish embryo-larval stage. Remarkably, the results demonstrated that polydatin up to 435 μM showed no toxicity. Throughout the exposure period, zebrafish embryos exposed to polydatin exhibited normal development, with no significant mortality observed. Furthermore, hatching success and heartbeat rate were unaffected, and no morphological abnormalities were identified, signifying a lack of teratogenic effects and cardiotoxicity. Locomotion activity assessment revealed normal swimming patterns and response to stimuli, indicating no neurotoxic effects. Our study provides valuable insights into the toxicological profile of polydatin, suggesting that it may offer potential therapeutic benefits under a considerable concentration range. In addition, zebrafish model proves to be an efficient system for early-stage toxicological screening, guiding further investigations into the secure utilization of polydatin for human health and wellness.

Clinical pharmacist intervention to ensure safe stimulant prescribing practices at a Veterans Affairs facility.

The Psychotropic Drug Safety Initiative (PDSI) is a national Veterans Affairs program that recommends obtaining cardiovascular vital signs semiannually and urine toxicology screening annually for veterans prescribed stimulants. The PDSI also recommends a risk review of concurrent central nervous system (CNS) depressants to ensure the benefits of coadministration with stimulants outweigh the risks. This project's purpose was to evaluate the occurrence of coprescriptions for CNS depressants and stimulants and encourage compliance with the PDSI recommendations to increase safe and appropriate management of veterans prescribed the combination. This study aimed to evaluate the occurrence of coprescriptions for CNS depressants and stimulants, evaluate compliance with stimulant monitoring recommendations, and measure the proportion of pharmacist recommendations implemented by the prescriber. This quality improvement project identified veterans with an outpatient prescription for a stimulant and any coprescription(s) for benzodiazepines, sedative-hypnotics, and/or opioids. A pharmacy intervention note was generated to request a risk review, provide recommendations for de-escalation, and notify the stimulant prescriber of overdue monitoring parameters. Impact was measured 60 days after intervention. Descriptive statistics and a McNemar test were used to compare preintervention and postintervention data. From the 61 patients included, there were 67 unique prescriptions for benzodiazepines (49.3%), sedative-hypnotics (34.3%), and opioids (16.4%) in combination with a stimulant. Pharmacist intervention resulted in de-escalation of coprescribing for 9 patients (16.1%) and was associated with statistically significant improvement in compliance to stimulant monitoring recommendations. Clinical pharmacists can assist in ensuring safe and appropriate monitoring and management of veterans prescribed stimulants.

Screening of the Antagonistic Activity of Potential Bisphenol A Alternatives toward the Androgen Receptor Using Machine Learning and Molecular Dynamics Simulation.

Over the past few decades, extensive research has indicated that exposure to bisphenol A (BPA) increases the health risks in humans. Toxicological studies have demonstrated that BPA can bind to the androgen receptor (AR), resulting in endocrine-disrupting effects. In recent investigations, many alternatives to BPA have been detected in various environmental media as major pollutants. However, related experimental evaluations of BPA alternatives have not been systematically implemented for the assessment of chemical safety and the effects of structural characteristics on the antagonistic activity of the AR. To promote the green development of BPA alternatives, high-throughput toxicological screening is fundamental for prioritizing chemical tests. Therefore, we proposed a hybrid deep learning architecture that combines molecular descriptors and molecular graphs to predict AR antagonistic activity. Compared to previous models, this hybrid architecture can extract substantial chemical information from various molecular representations to improve the model's generalization ability for BPA alternatives. Our predictions suggest that lignin-derivable bisguaiacols, as alternatives to BPA, are likely to be nonantagonist for AR compared to bisphenol analogues. Additionally, molecular dynamics (MD) simulations identified the dihydrotestosterone-bound pocket, rather than the surface, as the major binding site of bisphenol analogues. The conformational changes of key helix H12 from an agonistic to an antagonistic conformation can be evaluated qualitatively by accelerated MD simulations to explain the underlying mechanism. Overall, our computational study is helpful for toxicological screening of BPA alternatives and the design of environmentally friendly BPA alternatives.

Pre-disease detection of stress-associated disorders in combatants depending on professional activity profile

Relevance. Combat stress and other forms of stress-associated mental disorders, as well as their consequences currently remain a most urgent issue in military personnel directly or indirectly involved in armed conflicts. Active deployment of weapons for remote destruction of manpower and infrastructure has caused qualitative transformations in the profile of medical casualties, thus becoming a powerful stress factor of intense psychological pressure on personnel. The fundamentally new nature of armed confrontations, which in many ways is incompatible with domestic experience acquired over the recent decades during local hostilities in the "hot zones", is gaining relevance, as well as effective prevention and treatment of health disorders associated with combat mental trauma in the personnel deployed in the special military operation. The objective is to identify pre-disease characteristics of stress-associated disorders in combatants, depending on their professional activity profile.Methods. We examined 209 males earlier deployed in combat zones. All the examined combatants were divided in three groups according to professional criteria: group 1 – employees of the Ministry of Internal Affairs of Russia (n = 71); group 2 – soldiers of the National Guard of Russia (the Rosgvardiya) (n = 70); group 3 – employees of the EMERCOM of Russia (n = 68). Clinical and psychopathological examination with prior blood chemistry and toxicological screening were conducted to identify metabolites of psychoactive substances.Results and discussion. Although the research showed an elevated risk of post-traumatic stress disorder in the combatants across all the three groups, employees of the EMERCOM of Russia and the Ministry of Internal Affairs of Russia demonstrated average stress coping ability, whereas soldiers of the National Guard of Russia showed higher levels of maladaptation and greater susceptibility to subclinical anxiety and depressive disorders. Combatants directly involved in combat operations often resort to alcohol or sedatives.Conclusion. Programs for medical and psychological rehabilitation implemented as part of psychological and psychiatric prevention efforts shall be adjusted to the combatants’ professional profile with a specific focus on the type of combat service duties.

Inpatient Complications and Outcomes for Burn Patients Admitted With Methamphetamine Intoxication.

Methamphetamine intoxication frequently complicates inpatient burn admissions. While single-institution studies describe adverse outcomes during resuscitation, little is known about the risks of amphetamine intoxication on inpatient complications and perioperative management. The US National Trauma Data Bank was queried for burn encounters between 2017 and 2021. Amphetamine intoxication was identified on admission. Primary outcomes included death, stroke, and myocardial infarction (MI). Secondary outcomes included organ failure and surgical management. Multivariable regressions modeled outcomes adjusting for available covariates including demographics, TBSA burned, and inhalation injury. Bonferroni adjustments were applied. Our study identified a total of 73,968 primary burn encounters with toxicology screens. Among these, 800 cases (1.1%) were found to have positive methamphetamine drug screens upon admission. Methamphetamine users were significantly older (41.7 vs 34.9 years, P < .001), had a greater percentage of males (69.6 vs 65.4, P = .045), were more likely to have inhalation injury (P < .001), and had larger %TBSA burns (16% vs 13%, P < .001). Methamphetamine users were no more likely to die, experience MI, or experience stroke during admission. In contrast, methamphetamine users were significantly more likely to have alcohol withdrawal (P = .019), acute kidney injury (AKI) (P < .001), deep vein thrombosis (P = .001), pulmonary embolism (PE) (P = .039), sepsis (P = .026), and longer intensive care unit (ICU) stays (P < .001). Methamphetamine use was associated with a longer number of days to the first procedure (P = .005). Of all patients who required surgery (15.0%), methamphetamine users required significantly more total debridements and reconstructive procedures (P < .001). While not associated with mortality, methamphetamine intoxication was associated with an increased risk of many complications including PE, deep vein thrombosis, AKI, sepsis, and longer ICU stays. Methamphetamine intoxication was associated with delays in surgical care.

Metabolic profile of N-ethylhexedrone, N-ethylpentedrone, and 4-chloromethcathinone in urine samples by UHPLC-QTOF-HRMS

Forensic laboratories are constantly required to identify new drugs and their metabolites. N-ethylhexedrone (NEH, HEXEN), N-Ethylpentedrone (NEP), and 4-Chloromethcathinone (4-CMC, clephedrone) are synthetic substances structurally related to natural cathinone, alkaloid present in the leaves of the Catha edulis (Khat) plant. These synthetic cathinones (SC) are members of the heterogenous family of new psychoactive substances (NPS) that raised major concerns in scientific and forensic communities over the past years due to their widespread consumption. In this context, we investigated their metabolic profile using of UHPLC-QTOF-HRMS to elucidate the distribution of the parent drug and its metabolites in urine samples over time. Initially, both male and female volunteers were divided into three groups and eight subjects of each group were administered intranasally or orally with one SC (20–40 mg of NEH or NEP intranasal, 100–150 mg of 4-CMC oral). Urine samples were collected at 0–2 and 2–4 or 2–5 h. Urine (50 μL) was diluted 1:2 with acetonitrile/methanol (95:5) and injected into the UHPLC-QTOF-HRMS. Phase-I and phase-II metabolites were identified on the basis of fragmentation patterns and exact masses. Several phase-I and glucuronide-phase-II metabolites were identified in urine samples. Keto group reduction, hydroxylation and dealkylation were the common metabolic pathways identified for all cathinones and the presence of NEH-glucuronide, NEP-glucuronide and 4-CMC-glucuronide was also relevant. Significant is the slower metabolite formation for 4-CMC, which was detected at high concentrations in its original form even 5 h after administration, due to its long half-life and low intrinsic clearance compared to the other SCs. UHPLC-QTOF-HRMS demonstrated a considerable capability to semi-quantify the three synthetic cathinones and identify the target metabolites with high reliability. The introduction of new target compounds improves the efficiency of toxicological screening analysis on real samples and extends the window of detection of the SCs in biological matrices.

Factors Impacting Maltreatment Evaluation and Reports to Child Protective Services in Pediatric Substance Exposures.

The objective of this study was to assess demographic, clinical, and psychosocial factors associated with pediatric substance exposures, describe the medical evaluation, and identify factors associated with social work (SW) and hospital-based child protection team (CPT) safety assessments and reports to child protective services (CPS). We retrospectively reviewed charts of electronic medical records for children ages 0 to 72 months presenting for accidental ingestion evaluated May 1, 2015 to May 1, 2021 at a level 1 pediatric trauma center. Cases of environmental exposures, iatrogenic medication errors, dosing errors, and allergies/adverse reactions were excluded. Data were analyzed using descriptive statistics; χ 2 and multivariable logistic regression analysis assessed factors associated with two primary outcomes of interest, SW/CPT assessment and CPS report. Among 773 total cases of substance exposures during the studied time frame, 27% were referred to SW/CPT for further safety assessments and 15.4% were reported to CPS. Being admitted to the hospital, prescription medication or recreational/illegal/illicit substance exposures, and increasing psychosocial risk factors were found to be significantly associated with referrals. Age, race, and insurance status were not found to be associated. Toxicology screening was performed in only 24.7% of cases. Of those eligible for further imaging per hospital protocol, skeletal surveys were obtained in 5.5% of cases and head imaging was obtained in 9% of cases. There is significant variability in pediatric substance exposure assessment practices. Disparities based on demographic characteristics are uncommon. Perceived severity of condition, exposures involving recreational/illegal/illicit substances, and greater prevalence of family psychosocial adversities are associated with higher rates of SW/CPT assessment and CPS reports.

N-desethyl isotonitazene detected in polydrug users admitted to hospital in Birmingham, United Kingdom

Introduction Nitazenes are potent synthetic opioids and N-desethyl isotonitazene, a metabolite of isotonitazene, has emerged as a drug in its own right. Methods This is an observational case series of patients with suspected or declared substance use who were admitted to hospitals in the Sandwell and West Birmingham National Health Service Trust between July and October 2023. All patients were found on toxicological screening to have been exposed to N-desethyl isotonitazene. Results Twenty presentations involving 19 patients who tested positive for N-desethyl isotonitazene were included in the study. In 19 presentations, multiple substances were detected on toxicological screening. The number of patients testing positive for other substances were: 19 for cocaine and its main metabolite benzoylecgonine, 13 for morphine, 11 for the heroin-specific metabolite 6-monoacetylmorphine, ten for xylazine, eight for gabapentinoids (pregabalin and/or gabapentin), seven for methadone and/or the metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, six for benzodiazepines and five for the synthetic cannabinoid MDMB-4en-PINACA. Only one patient had no other substances detected apart from N-desethyl isotonitazene. This patient presented with coma, miosis, bradypnoea and hypercapnia and responded to naloxone. In this cohort, the median concentration of N-desethyl isotonitazene was 1.53 µg/L (n = 14; range 0.59–5.48) in whole blood and 27.75 µg/L (n = 16; range 0.51–91.53) in urine. Discussion The majority of the patients in this cohort presented with features typical of an opioid overdose, which is unsurprising as they were all experienced users of diamorphine. Although these features are also consistent with the known effects of N-desethyl isotonitazene, in only one case is it possible to attribute the patient’s features to N-desethyl isotonitazene toxicity alone. Conclusions This case series highlights the need for toxicovigilance in the illicit drug market as patterns of substance misuse evolve and novel psychoactive substances continue to emerge.

Discovery of novel coumarin triazolyl and phenoxyphenyl triazolyl derivatives targeting amyloid beta aggregation-mediated oxidative stress and neuroinflammation for enhanced neuroprotection.

This study involved designing, synthesizing, and evaluating the protective potential of compounds on microglial cells (BV-2 cells) and neurons (SH-SY5Y cells) against cell death induced by Aβ1-42. It aimed to identify biologically specific activities associated with anti-Aβ aggregation and understand their role in oxidative stress initiation and modulation of proinflammatory cytokine expression. Actively designed compounds CE5, CA5, PE5, and PA5 showed protective effects on BV-2 and SH-SY5Y cells, with cell viability ranging from 60.78 ± 2.32% to 75.38 ± 2.75% for BV-2 cells and 87.21% ± 1.76% to 91.55% ± 1.78% for SH-SY5Y cells. The transformation from ester in CE5 to amide in CA5 resulted in significant antioxidant properties. Molecular docking studies revealed strong binding of CE5 to critical Aβ aggregation regions, disrupting both intra- and intermolecular formations. TEM assessment supported CE5's anti-Aβ aggregation efficacy. Structural variations in PE5 and PA5 had diverse effects on IL-1β and IL-6, suggesting further specificity studies for Alzheimer's disease. Log P values suggested potential blood-brain barrier permeation for CE5 and CA5, indicating suitability for CNS drug development. In silico ADMET and toxicological screening revealed that CE5, PA5, and PE5 have favorable safety profiles, while CA5 shows a propensity for hepatotoxicity. According to this prediction, coumarin triazolyl derivatives are likely to exhibit mutagenicity. Nevertheless, CE5 and CA5 emerge as promising lead compounds for Alzheimer's therapeutic intervention, with further insights expected from subsequent in vivo studies.

Urine toxicology screen: What challenges?

Urine toxicology screen: What challenges?