Potential Misuse Research Articles

Dispensing of zolpidem and benzodiazepines in Brazilian private pharmacies: a retrospective cohort study from 2014 to 2021

ObjectiveThe study aimed to evaluate Zolpidem and Benzodiazepines prescription and dispensing data in private pharmacies in Brazil from 2014 to 2021. Methods: This retrospective cohort study was carried out with retrospective open data from the Brazilian Federal Government from January 2014 to August 2021 containing medicines registered in the National Controlled Products Management System (SNGPC).ResultsBetween January 2014 and August 2021, a total of 32,441,392 sales of thirteen drugs from the z-drug and benzodiazepine classes used to treat sleep disorders were recorded in Brazil. Throughout the entire period, clonazepam emerged as the most popular drug, accounting for 29.8% of total sales. Alprazolam followed in second place with 20.6% of sales, while zolpidem came in third with 14.4%. The normal-release form of zolpidem was consistently the highest-selling variant during the evaluation period. However, the fast-acting-release form exhibited the most significant growth, indicated by a noticeable upward trend in sales since 2020. In contrast, the extended-release form of zolpidem remained stable over the years.ConclusionThe increased sales of zolpidem in Brazilian private pharmacies raise concerns about potential misuse and dependence on this drug mainly for the treatment of insomnia. The epidemic of sleeping pills arises in a scenario of expectancy of short-term amelioration of symptoms, with no correspondence in best clinical practice. Education and counseling for both healthcare professionals and the general population are essential to address this growing health concern and ensure the safe and appropriate use of medications for sleep disorders.

Maintaining Integrity and Confidentiality of Patients’ Records Using an Enhanced Security Technique

Medical record storage on paper is currently being phased out and replaced by more sophisticated Electronic Health Record (EHR) systems. However, the ease of access to data and the digitization of medical records also come with the potential of misuse of personally identifiable information and healthcare data breaches. How technology will protect patient privacy is one of the primary concerns about EHRs. Network connectivity is another major issue, therefore keeping private health information online may expose it to major information leaks to external parties. Around the world, data management and privacy are major concerns. The main concerns that prevent businesses from using cloud computing are security and information authenticity, as they fear that data may be lost to unauthorized parties. The quantity of patient-oriented data in the healthcare system is continuously increasing, and the current medical systems are confronted with security issues such as weak access control, data breaches or unauthorized disclosure, and insufficient authorization and authentication. An Enhanced Security Model was created in this study to secure and protect Electronic Health Records. The records were encrypted for security and privacy utilizing the Advanced Encryption Standard (AES), One Time Password (OTP), and National Identity Number (NIN). The system was designed using Object Oriented Analysis and Design Methodology (OOADM). The New System improved patient record security by utilizing NIN for cloud identity management, OTP for authentication, and AES for privacy and security. While the MySQL server was used to implement the database, HTML, CSS, PHP, and JavaScript were used to program the system. Comparing the new system to the old system, the results of the performance assessment analysis based on security, user-friendliness, dependability, and privacy show that the new system has very good performance efficiency and integrity.

The NIH Pain Common Data Elements: A Great Start but a Long Way to the Finish Line.

The NIH Pain Common Data Elements (CDEs) provide a standardized framework for pain research, but their implementation and interpretation present challenges. To review the NIH CDE Program's selected pain domains, provide best practices for implementing required questions, and offer a checklist for appropriate CDE use in clinical trials and secondary data analysis. This work analyzed the ten core pain research domains selected by the NIH CDE Program and discuss their limitations and considerations for use. The manuscript provides an overview of the ten core pain research domains, including pain intensity, interference, physical function, sleep, catastrophizing, depression, anxiety, global impression of change, substance use screening, and quality of life. It offers sample scenarios for implementing required questions and presents a checklist to guide researchers in using pain CDEs effectively for clinical trials and secondary data analysis. Key challenges identified include contextual variability, lack of validation across all pain conditions and populations, and potential misuse or misinterpretation of measures. This work proposes solutions such as supplementary measures, context-specific guidance, comprehensive training programs, and ongoing refinement of the CDE framework. While NIH Pain CDEs are valuable tools for standardizing pain assessment in research, addressing challenges in their implementation and interpretation is crucial for improving the consistency, validity, and interpretability of pain research data, ultimately advancing the field and enhancing patient care.

The Impact of Hate Speech Regulations on Freedom of Expression an Indonesian Legal Perspective

This paper explores the impact of hate speech regulation on freedom of expression in Indonesia from a juridical perspective. The study focuses on the legal framework, including the Electronic Information and Transactions Law (UU ITE) and the Indonesian Penal Code (KUHP), both of which are central to the regulation of hate speech. Through an analysis of key statutes, court rulings, and case studies, this paper highlights the tension between protecting public order and safeguarding free speech. The findings reveal that vague legal definitions and broad enforcement of hate speech laws have led to selective prosecution, often targeting political dissent and criticism. These issues raise concerns about the erosion of democratic rights and the potential misuse of hate speech laws for political purposes. Recommendations are provided to clarify legal definitions, ensure proportionality in enforcement, and prevent the misuse of these laws in a manner that balances the protection of social harmony with the preservation of freedom of expression.

Testing the capacity of Bard and ChatGPT for writing essays on ethical dilemmas: A cross-sectional study

Recent advancements in artificial intelligence (AI) have led to concerns about its potential misuse in education. As large language models (LLMs) such as ChatGPT and Bard can generate human-like text, researchers and educators noted the potential redundancy of tasking students with writing academic essays. We aimed to explore if the two LLMs could generate unstructured essays on medical students’ personal experiences of challenges and ethical dilemmas that are indistinguishable from human-written texts. We collected 47 original student-written essays from which we extracted keywords to develop prompts for the LLMs. We then used these prompts to generate an equivalent number of essays using ChatGPT and Bard. We analysed the essays using the Language Inquiry and Word Count (LIWC) 22 software, extracting the main LIWC summary measures and variables related to social and psychological processes. We also conducted sub-analyses for sixteen student essays that were presumably written entirely or in part by AI, according to two AI detectors. We found that AI-written essays used more language related to affect, authenticity, and analytical thinking compared to student-written essays after we removed AI-co-written student essays from the analysis. We observed that, despite the differences in language characteristics compared to student-written essays, both LLMs are highly effective in generating essays on students’ personal experiences and opinions regarding real-life ethical dilemmas.

Frequency and mechanism of injury for unintentional paediatric femoral fractures associated with consumer products over a 10-year period in the USA.

Femoral shaft fractures tend to be rare among children; however, these injuries are the most common major paediatric injuries treated by orthopaedic surgeons. The purpose of this study is to characterise the demographics and mechanisms of femoral injury associated with consumer products in the age group treated with spica casting, children 6 months to 6 years, to identify areas for injury prevention. Data from 2012 to 2021 were obtained from the National Electronic Injury Surveillance System maintained by the Consumer Products Safety Commission, documenting emergency department visits for unintentional injuries associated with consumer products. Narrative descriptions were analysed to identify common factors in the injury events such as location, products and mechanisms of action. From 2012 to 2021, the estimated incidence of femur fractures was 23.5 cases per 100 000 children with no significant difference in yearly frequency. The most common mechanism of injury was a fall with the most frequent fracture sources being bed/bunk beds (16.1%), floor (slips/falls, 9.7%) and trampolines (9.7%). Most fractures occurred at the patient's home (58.4%). The incidence of injury outside of the home and frequency of fractures involving play structures/trampolines increased with age. The incidence and demographic characteristics of paediatric femur fractures associated with consumer products have remained consistent over the past 10 years. As home was the most common location of fracture, prevention of femur fractures should focus on caregiver education around high-risk sources of fracture (bed, stairs and trampolines) and manufacturers should consider design alternatives that discourage potential misuse.

Review of Guidelines on Bupropion for Depression

What Is the Issue? Bupropion is a drug used in the treatment of depression. Bupropion is 1 of many treatment options available for depression and is associated with several side effects as well as the potential for misuse. Some patients continue to experience symptoms of depression despite trying multiple medications (known as treatment-resistant depression). Therefore, it is important to determine the place in therapy of bupropion for the treatment of depression. What Did We Do? To help determine the potential place in therapy for bupropion for the treatment of major depressive disorder (MDD) and treatment-resistant depression in adults, we sought to identify and summarize recommendations in evidence-based guidelines. We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included publications, and narratively summarized the findings. What Did We Find? We identified 4 evidence-based guidelines that included recommendations on the use of bupropion for MDD. We identified 1 evidence-based guideline that included a recommendation on the use of bupropion for difficult-to-treat depression (defined as persistent depression despite several standard treatments). All 4 included guidelines recommend bupropion for the treatment of adults with MDD. Two of the guidelines recommend bupropion as a first-line treatment option. One guideline suggests bupropion as an option for initial pharmacologic treatment or for patients who have previously responded well to pharmacotherapy. One guideline suggests bupropion as an option for adjunctive treatment for patients in the acute phase of moderate to severe MDD who did not respond to treatment with a second-generation antidepressant. One guideline suggests bupropion as a second-line adjunctive option for adults with difficult-to-treat depression. What Does It Mean? The included evidence-based guidelines consistently recommend bupropion as an option for the treatment of adults with MDD. Additional factors such as the availability of other options, costs, and patient preferences may also be important to decision-making around the use of bupropion for MDD. Only 1 of the included guidelines included a recommendation on the use of bupropion for patients with difficult-to-treat depression. Future evidence-based guidelines that include recommendations on the use of bupropion for treatment-resistant depression would help fill the gaps identified in this report.

Effect of sacubitril/valsartan and dapagliflozin on athletic performance; can the popular cardiac medications of recent years be used as doping agents?

Abstract Background/Introduction Recent guidelines have highlighted the positive impacts of sacubitril/valsartan and dapagliflozin on heart failure management [1]. Given their potential misuse as doping agents in professional sports, this study evaluates their effects on athletic performance. Purpose To investigate the effects of sacubitril/valsartan and dapagliflozin on athletic performance and cardiac functions in a rodent model. Methods The study had a randomized double-blind design. 24 Sprague-Dawley male rats aged 4 months, divided into control, sacubitril/valsartan, and dapagliflozin groups. The rats were weighed at the start of the experiment. The medications (dapagliflozin 1,5 mg/kg/1 ml/once a day, sacubitril/valsartan 60 mg/kg/1 ml/once a day to their respective groups, and normal saline for control group) were administered via gastric gavage for 30 days. The rats were weighed, examined with transthoracic echocardiography and put on rotarod at the start of the experiment, and on 15th and 30th days. The rats were put on forced swimming tests for 20 days. Exhaustion, loss of coordinated movements and failure to surface for 3 seconds after submersion in the water were defined as indications for ending the test as per the guidelines regarding rat exercise testing [2]. M-mode and Doppler measurements, forced swimming test durations, rotarod durations and weight were recorded on 0th, 15th and 30th days. Results Initial performance metrics, including echocardiography, weight, and rotarod tests, showed no significant differences among the groups at baseline. The distributions in data were non-normal. Over the course of the study, median swimming times significantly differed from the 9th session, with dapagliflozin-treated rats exhibiting a substantial increase in endurance. Specifically, dapagliflozin group's swimming times increased to a median of 3580 seconds by the 20th session, compared to 2382 seconds in the control group and 2591 seconds in the sacubitril/valsartan group, indicating a pronounced improvement in exercise capacity (P<0.0001)(Figure-1). Echocardiographic assessments revealed enhanced cardiac output and ejection fraction, particularly in the sacubitril/valsartan group, suggesting increased cardiac efficiency and potential athletic performance enhancement. Conclusion(s) The study demonstrates a significant improvement in athletic performance with dapagliflozin compared to sacubitril/valsartan. These findings suggest a potential for misuse in sports doping, emphasizing the need for stringent regulation and monitoring within competitive athletics.Figure-1

An Early Snapshot of Attitudes Toward Generative Artificial Intelligence in Physical Therapy Education

Introduction. Generative artificial intelligence (AI) is rapidly gaining popularity across health care, education, and society. The purpose of this study was to assess perceptions and use of generative AI in academic physical therapy (PT). Review of Literature. Generative AI became one of the fastest-growing technologies ever after the public release of ChatGPT in November 2022. Early data indicate that attitudes toward generative AI in higher education are mixed and rapidly evolving, with significant ethical concerns around use and potential misuse. There are no published studies investigating perceptions and use of generative AI in PT education. Subjects. A total of 175 surveys were completed and analyzed. Respondents included PT educators, administrators, and students. Methods. An anonymous, online survey on use and perception of AI was distributed through email and social media. Descriptive statistics and cross-tabulations were performed to analyze respondent characteristics and responses to survey questions. Results. Most respondents (61.1%) reported they did not use generative AI during the 2022-2023 academic year, whereas 35.4% were generative AI users. More than 40% of respondents were optimistic or very optimistic toward generative AI. Users of AI were more likely to report an optimistic or very optimistic disposition toward AI compared with nonusers. AI users were more likely to agree or completely agree that generative AI has more benefits than drawbacks compared with nonusers. Discussion and Conclusion. Results of this survey suggest that, despite the rapid uptake of generative AI in society, many PT educators and students harbor reservations and uncertainties toward its use. Artificial intelligence users were less likely to hold negative perceptions toward it and were more likely to find it useful. Understanding use and perceptions of generative AI in PT education may inform strategies to promote innovation, policy-making, and ethical integration of this new and rapidly evolving technology.

Neurorights in the Constitution: from neurotechnology to ethics and politics.

Neuroimaging technologies such as brain-computer interfaces and neurofeedback have evolved rapidly as new tools for cognitive neuroscience and as potential clinical interventions. However, along with these developments, concern has grown based on the fear of the potential misuse of neurotechnology. In October 2021, Chile became the first country to include neurorights in its Constitution. The present article is divided into two parts. In the first section, we describe the path followed by neurorights that led to its inclusion in the Chilean Constitution, and the neurotechnologies usually involved in neurorights discussions. In the second part, we discuss two potential problems of neurorights. We begin by pointing out some epistemological concerns regarding neurorights, mainly referring to the ambiguity of the concepts used in neurolegislations, the difficult relationship between neuroscience and politics and the weak reasons for urgency in legislating. We then describe the dangers of overprotective laws in medical research, based on the detrimental effect of recent legislation in Chile and the potential risk posed by neurorights to the benefits of neuroscience development. This article aims to engage with the scientific community interested in neurotechnology and neurorights in an interdisciplinary reflection of the potential consequences of neurorights.This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.

Driving performance and ocular activity following acute administration of 10 mg methylphenidate: A randomised, double-blind, placebo-controlled study.

Methylphenidate is a routinely prescribed treatment for attention-deficit/hyperactivity disorder with misuse potential owing to its perceived performance-enhancing and euphoric properties. Although clinically effective, there is limited understanding of how methylphenidate affects safety-sensitive tasks such as driving when used by healthy individuals. Explore the acute effects of 10 mg methylphenidate on driving performance and gaze behaviour. Twenty-five fully licensed, healthy adults (mean age = 33.5 ± 7.8 years, 64% male) took part in two 40-min simulated highway drives with simultaneous eye movements monitored using a proprietary automotive-grade driver monitoring system (Seeing Machines). Driving performance was assessed using the standard deviation of lateral position, standard deviation of speed and steering variability. Visual scanning efficiency was determined using ocular metrics, such as fixation duration and rate, gaze transition entropy, and stationary gaze entropy, were assessed to determine visual scanning efficiency. Methylphenidate significantly improved driving performance by reducing lane weaving and speed variation, particularly in the latter half of the drive. Although a significant reduction in fixation duration was observed, all other ocular metrics remained unchanged. Methylphenidate mitigates performance decrements typically associated with prolonged and monotonous driving. The absence of pronounced oculomotor effects suggests that a single 10 mg dose of methylphenidate has no deleterious impact on visual scanning behaviour during driving tasks with low-to-moderate cognitive demand. Future research should investigate the effects of methylphenidate under various dosing and driving conditions to better understand its impact. ACTRN12620000499987.

Simultaneous detection of myostatin-targeting monoclonal antibodies in dried blood spots and plasma using liquid chromatography-tandem mass spectrometry with field asymmetric ion mobility spectrometry

Transforming growth factor-β superfamily members, such as myostatin, growth/differentiation factor 11, and activin A, negatively regulate skeletal muscle mass. Inhibitors targeting these cytokines or activin receptor type IIB have the potential to treat muscular diseases and enhance physical performance. However, because of their effects on muscle mass and potential misuse, they are strictly prohibited in sports. Given the high potential for misuse as a doping agent in sports, effective analytical methods for these prohibited antibodies targeting these specific cytokines or their receptor are critically needed. In this study, we aimed to develop and validate a multitarget method to detect the prohibited transforming growth factor-β superfamily-targeting monoclonal antibodies, such as landogrozumab, domagrozumab, and the activin receptor type IIB-targeting antibody, bimagrumab, in human plasma and dried blood spot (DBS) samples using liquid chromatography-tandem mass spectrometry. Antibodies were purified from both the DBS and plasma samples using protein G magnetic beads and field-asymmetric ion mobility spectrometry (FAIMS) to minimize interference, followed by liquid chromatography-tandem mass spectrometry analysis. The validation process included tests for specificity, selectivity, linearity, limit of detection (LOD), limit of identification, precision, recovery, carryover effect, and matrix effect. The LODs for the target antibodies were identical in both DBS and plasma samples at 0.1 µg/mL for landogrozumab heavy and light chains, as well as 0.25 µg/mL for the domagrozumab light chain and 0.25 µg/mL for the bimagrumab heavy chain. However, the heavy chain of domagrozumab exhibited an LOD of 0.5 µg/mL in DBS and 1 µg/mL in plasma. The analytical method demonstrated strong linearity, with R² values greater than 0.99 for both plasma and DBS, and no carryover effect. Precision (CV%) was below 15 % at both middle (1 or 5 µg/mL; specific to the heavy chain of domagrozumab in plasma) and high (10 µg/mL) concentrations and was less than 20 % at the LOD. The selectivity and specificity indicated no interference in the analysis of target mAbs in different blood samples. Recovery was 31.6–49.8 % for DBS and 51.4–85.3 % for plasma, with no significant matrix effect. This study provides an effective method for doping analysis and novel protein detection.

Legal Perspective on Consumer Personal Data Protection in Fintech Services

The development of science and technology has significantly affected the financial transaction system in Indonesia, especially with the emergence of the Fintech business model. The rapid growth of Fintech indicates the need for smart management in order to provide optimal benefits to society. However, the potential misuse of consumers' personal data poses a risk that needs to be considered. This research uses a normative juridical and analytical descriptive approach to understand the legal dynamics in the Fintech industry and legal measures aimed at Safeguarding user data security in Indonesia, in accordance with the provisions of Financial Services Authority Regulation Number 13/Pojk.02/2018. The results show that Fintech business organizers and users have a relationship that is regulated through an electronic agreement. The legal safeguarding of personal data for Fintech user is governed by Financial Services Authority Regulation Number 1/Pojk.07/2013 and other pertinent regulations, addressing aspects such as confidentiality, data security, and the governance and risk management of information technology.

Insights into Drug Donation Practices and Public Perceptions in Saudi Arabia

Background: Effective medication management, disposal, and donation are vital for public health and environmental sustainability. Improper handling of medications can lead to drug misuse, accidental poisoning, and environmental damage. This study examines current practices and challenges in Saudi Arabia, identifying opportunities for improvement. Method: A cross-sectional survey conducted in October and November 2023 targeted the general population in Saudi Arabia. This study employed convenience sampling to explore medication usage, storage, disposal practices, and awareness of donation procedures. Data were analyzed through both descriptive and inferential statistical methods. Results: This study involved 430 respondents. Of these, 73.0% held a university degree, yet 66.3% were unaware of drug donation programs, and 84.2% lacked knowledge about proper medication disposal. Despite this, 71.4% believed that drug donation programs positively impact healthcare, and 87.9% saw them as reducing drug waste and environmental pollution. However, 48.1% expressed concerns about the potential misuse of donated medicines. Awareness and knowledge were significantly higher among participants aged 30 and above. Conclusions: The findings highlight the need for enhanced public awareness, clear medication disposal guidelines, and ethically governed donation practices in Saudi Arabia. These measures can improve healthcare outcomes, protect the environment, and support global health and sustainability goals.

Scope of practice and opioid prescribing behavior of nurse practitioners serving Medicare beneficiaries.

Policymakers aiming to increase access to health care while simultaneously keeping costs low and quality high are considering expanding the practice authority and prescriptive authority of nurse practitioners in order to address primary care shortages. While we know this increases access, some researchers argue that the expansion of job autonomy of nurse practitioners can compromise the quality and safety of rendered medical services. This paper investigates quality and safety outcomes in prescribing behaviors of nurse practitioners who have prescribed opioids for Medicare Part D beneficiaries using a unique source of policy variation, nurse practitioners with the ability to prescribe medication who move to either states with or without physician supervision. We find that scope of practice expansions do not compromise quality and safety in terms of potential abuse or misuse of prescriptive authority.

B-271 High Sensitivity Homogeneous Enzyme Immunoassay for Benzodiazepines and Metabolites

Abstract Background Benzodiazepines are widely prescribed for treating various conditions such as anxiety, insomnia, and seizures due to their sedative and anxiolytic properties. Despite their therapeutic benefits, concerns persist regarding their potential for misuse, dependence, and addiction. Urine drug screening immunoassays serve as an important tool in monitoring benzodiazepine usage, ensuring adherence to prescribed regimens, identifying misuse or abuse, and facilitating necessary medical interventions. However, limitations of benzodiazepine immunoassays are well-documented in literature, with issues surrounding their lack of sensitivity to glucuronidated and 7-amino metabolites, inability to detect newer benzodiazepines, and poor cross-reactivity with different benzodiazepines. ARK Diagnostics has developed a highly sensitive homogeneous enzyme immunoassay capable of detecting both classic and designer benzodiazepines, in addition to their glucuronide and 7-amino metabolites in human urine at a cutoff concentration 200 ng/mL, without the need for glucuronidase or sample pretreatment. Methods The ARKTM Benzodiazepine Plus Assay is a liquid-stable homogenous enzyme immunoassay consisting of two reagents. The assay uses temazepam as the 200 ng/mL cutoff calibrator. The performance characteristics of this assay, including precision, spiked recovery, specificity, and method comparison to LC-MS/MS, were evaluated on the Beckman Coulter AU680 automated clinical analyzer. Results The ARKTM Benzodiazepine Plus demonstrated acceptable precision, with no overlap between cutoff (200 ng/mL) and ±25% control levels (150 ng/mL and 250 ng/mL) in a histogram overlap analysis, and ≤3.6% CV in semi-quantitative mode. Spiked temazepam samples spanning the semi-quantitative assay range of 1000 ng/mL were recovered between 95.0% and 103.7% of the spiked levels. Thirty-eight benzodiazepines produced cross-reactivities >80%, including the following benzodiazepines and metabolites: lorazepam, clonazepam, diazepam, alprazolam, temazepam, oxazepam glucuronide, lorazepam glucuronide, temazepam glucuronide, 7-aminoclonazepam, and 7-aminoflunitrazepam. In method comparison studies, a total of 103 urine samples containing benzodiazepines with LC-MS/MS values ranging from 1.3 ng/mL to 3257.6 ng/mL were tested with the ARKTM Benzodiazepine Plus Assay. Eighty samples tested positive with values ≥200 ng/mL and 23 samples tested negative with values <200 ng/mL by the ARKTM Benzodiazepine Plus assay. Of the 23 samples that tested negative, 21 had LC-MS/MS values <200 ng/mL and 2 samples were identified as midazolam samples with metabolite a-OH-midazolam levels >200 ng/mL. Conclusions The ARKTM Benzodiazepine Plus Assay enables the sensitive, rapid, and reliable measurement of benzodiazepines and their metabolites in human urine, without the need for hydrolysis or pretreatment. The assay addresses the present constraints of currently available benzodiazepine immunoassays, including their insufficient sensitivity, limited cross-reactivity to metabolites, and the requirement for glucuronidase pretreatment. The ARKTM Benzodiazepine Plus Assay is applicable to a wide range of clinical chemistry analyzers.

B-269 Development and CYP3A4 Characterization of a Population-based Urinary Buprenorphine and Norbuprenorphine Nomogram

Abstract Background Buprenorphine (Bup), routinely prescribed for opioid use disorder, metabolizes to norbuprenorphine (NBup) primarily via cytochrome P450 (CYP) 3A4. Confirmation of urinary Bup and NBup helps monitor patient adherence to therapy and potential misuse. This study aims to develop and characterize a population-based urinary NBup/Bup nomogram using pharmacogenetics (PGx) to facilitate opioid result interpretations. Methods Adult urinary Bup and NBup results between 09/01/2022 and 09/30/2023 at UNC Health were retrieved from the EMR. Results outside the clinically reportable range (CRR; 5-25,000 ng/mL) were assigned the lower or upper CRR value, respectively. A scatterplot of Bup versus NBup/Bup on logarithmic scale was generated using Excel. Buffy coats from 14 EDTA whole blood samples were extracted and isolated using EasySep buffer (StemCell) with centrifugation at 8000rpm for 10 minutes without braking and stored at -80°C until shipment to DHMC. Genomic DNA was extracted using an EZ1 DNA procedure (Qiagen) and libraries (Agilent SureSelect) were prepared by hybridization capture of a custom PGx panel. Paired-end sequencing was performed on a MiSeq prior to diplotype-metabolizer function assignments in AUGMET. 22 CYP3A4 gene hotspots were detected by NGS and analyzed for gene-drug-variant relationships. Results 3593 results from 896 patients were retrieved. The NBup/Bup nomogram revealed 3 subgroups from this population (Figure). CYP3A4 genotyping showed 13 wildtype calls and 1 CYP3A4 *1/*22 star allele genotype, with reduced enzyme activity. Wildtype results corresponded with Bup/NBup in subgroups 1(n=1), 2 (n=11) and 3 (n=1); CYP3A4 *1/*22 result corresponded with subgroup 3. Conclusions We developed a novel NBup/Bup nomogram revealing 3 subgroups in our patient population. Overlap of wildtype CYP3A4 in subgroups 1, 2 and 3 as well as CYP3A4 *1/*22 genotype in subgroup 3 suggest the NBup/Bup subgroups are independent of CYP3A4 phenotype. The characterization of population-based urinary NBup/Bup nomogram shows promise for aiding in opioid result interpretations.

B-257 Dont go breaking my heart: use and misuse of beta-blockers in clinical and forensic casework (2019-2023)

Abstract Background Beta-adrenergic antagonists, or beta-blockers, are commonly prescribed for the treatment and prevention of a variety of cardiovascular issues and other health conditions. These include, but are not limited to heart failure, heart rhythm disturbances, high blood pressure, hypertension, anxiety, asthma, glaucoma, and migraines. Beta-blockers work by blocking access to beta-receptors, which then enhance or inhibit cellular activity and result in dilating blood vessels and relaxing the heart muscle. When misused, accidentally or intentionally, serious adverse effects including dizziness, seizure, heart failure, QTc prolongation, coma, and death can occur. In routine toxicology testing, beta-blockers are often reported qualitatively, which likely underestimates the reporting of related adverse events. We performed a retrospective review to evaluate quantitative levels of beta-blockers in blood and identify trends of potential misuse. Methods We queried our laboratory’s data management system from 2019-2023 for reported findings of beta-blockers in blood. Analytes were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results were analyzed using Microsoft Office software. Results Blood results and a comparison of known therapeutic and adverse concentrations are shown in Table 1. Age and sex were reported in 50% and 74% of cases, respectively. Average age ranged from 43 years old (propranolol) to 59 years old (atenolol and metoprolol), without major differences between sexes. Overall use of beta-blockers was split evenly between men and women. Importantly, each analyte provided examples which far exceeded known therapeutic levels, with several cases submitted as potential overdoses. Conclusions Since beta-blockers are generally reported qualitatively during routine toxicology testing, concentrations are unknown. Quantitative testing has shown that beta-blocker concentrations often exceed known therapeutic ranges, which can lead to adverse effects and fatal outcomes. Physicians and death investigators should be aware of these adverse effects and the need for specialized testing in the event of suspected beta-blocker toxicity.

N-tert-butoxycarbonyl-methylenedioxymethamphetamine, an methylenedioxymethamphetamine derivative, exhibits rewarding and reinforcing effects by increasing dopamine levels.

An N-protected methylenedioxymethamphetamine (MDMA), N-tert-butoxycarbonyl-3,4-methylenedioxymethamphetamine (t-BOC-3,4-MDMA), contains tert-butoxycarbonyl and can remain undetected in the illicit drug market. It is a new type of precursor substance that is not a chemical intermediate and can be converted into a controlled substance, MDMA, by deprotection of the N-tert-butoxycarbonyl group. Categorization of this chemical into a precursor or psychotropic substance is an issue because it is an unprecedented precursor that could have misuse potential. Although MDMA causes rewarding and reinforcing effect through dopaminergic transmission, the misuse potential of t-BOC-3,4-MDMA has not yet been characterized. Here, we aim to evaluate the misuse potential of t-BOC-3,4-MDMA. The response to the drug at a dose of 5 mg/kg was determined by a climbing test, and its rewarding and reinforcing properties were assessed through conditioned place preference and self-administration tests. In the conditioned place preference test, intraperitoneal administration of t-BOC-3,4-MDMA (5 mg/kg) significantly altered place preference in mice. In the self-administration models, t-BOC-3,4-MDMA induced drug-taking behavior at the dose of 0.5 mg/kg/infusion (intravenous) during 2 hr sessions under fixed-ratio schedules in mice. In addition, microdialysis experiments verified that t-BOC-3,4-MDMA impacted the dopamine levels of the brain (striatum) of rats. These experimental results indicate that t-BOC-3,4-MDMA has a potential for misuse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Virulence of Burkholderia pseudomallei ATS2021 Unintentionally Imported to United States in Aromatherapy Spray.

In the United States in 2021, an outbreak of 4 cases of Burkholderia pseudomallei, the etiologic agent of melioidosis and a Tier One Select Agent (potential for deliberate misuse and subsequent harm), resulted in 2 deaths. The causative strain, B. pseudomallei ATS2021, was unintentionally imported into the United States in an aromatherapy spray manufactured in India. We established that ATS2021 represents a virulent strain of B. pseudomallei capable of robust formation of biofilm at physiologic temperatures that may contribute to virulence. By using mouse melioidosis models, we determined median lethal dose estimates and analyzed the bacteriologic and histopathologic characteristics of the organism, particularly the potential neurologic pathogenesis that is probably associated with the bimABm allele identified in B. pseudomallei strain ATS2021. Our data, combined with previous case reports and the identification of endemic B. pseudomallei strains in Mississippi, support the concept that melioidosis is emerging in the United States.