Identification and biophysical characterization of a novel domain-swapped camelid antibody specific for fentanyl.

Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression. To explore antibody applications beyond traditional heavy-light chain mAbs, we identified and biophysically characterized a novel single-domain antibody specific for fentanyl from a camelid variable-heavy-heavy (VHH) domain phage display library. Structural data suggested that VHH binding to fentanyl was facilitated by a unique domain-swapped dimerization mechanism, which accompanied a rearrangement of complementarity-determining region loops leading to the formation of a fentanyl-binding pocket. Structure-guided mutagenesis further identified an amino acid substitution that improved the affinity and relaxed the requirement for dimerization of the VHH in fentanyl binding. Our studies demonstrate VHH engagement of an opioid and inform on how to further engineer a VHH for enhanced stability and efficacy, laying the groundwork for exploring the in vivo applications of VHH-based biologics against OUD and overdose.

Suicide Deaths Involving Opioid Poisoning in the United States by Sex, 1999 - 2021.

Suicide remains a leading cause of death in the United States, and recent data suggests that suicide deaths involving opioids are increasing. Given unprecedented increases in drug poisoning deaths, suicidality, and suicide deaths in recent years, an updated examination of the trends in suicide deaths involving opioids is warranted. In this descriptive epidemiologic analysis, we leverage final and provisional mortality data from CDC WONDER to examine trends in suicide deaths involving opioid poisoning from 1999 - 2021 by biological sex. Results reveal complex changes over time: the number and age-adjusted rate of suicide deaths involving opioid poisoning among male and female residents tended to track together, and both increased through 2010, but then diverged with the number and rate of suicide deaths involving opioid poisoning among female residents outpacing that of male residents. However, the number and rate of suicide deaths involving opioid poisoning among male residents then began to stabilize, while that of female residents declined, closing the sex-based gap. Across all years of data, the proportion of suicide deaths that involved opioid poisoning was consistently higher among female decedents (5.8% - 11.0%) compared to male decedents (1.4% - 2.8%). Findings have implications for improved suicide prevention and harm reduction efforts.

Trends in and characteristics of drug overdose morbidity among pregnant and postpartum individuals in California, 2010-2018.

Fatal drug overdoses among pregnant and postpartum individuals have risen dramatically over the past 10 years. Trends in and characteristics of nonfatal drug overdoses in this population, however, remain unknown, despite the importance of this outcome for maternal and infant health. We used statewide, longitudinally-linked hospital and emergency department administrative claims data from California to characterize the incidence, trends, drug type involvement, and sociodemographic disparities in pregnancy-associated drug overdose between 2010 and 2019. Generalized linear models accounting for multiple deliveries per individual were used to test for trends; descriptive statistics were used for other study analyses. Of California individuals with a live delivery between 2010 and 2018, approximately 0.2% had a pregnancy-associated drug overdose. Nonfatal overdoses were nearly 60 times more common than fatal overdoses. Incidence of overdoses involving stimulants increased in frequency, while incidence of overdoses involving sedative/hypnotic drugs and psychotropic medications decreased in frequency. Risk of overdose was substantially higher among delivering individuals who were young, non-Hispanic Black, Medicaid patients, or who lived in non-metropolitan areas. Ongoing public health surveillance of and clinical interventions to reduce pregnancy-associated nonfatal drug overdose events are critical for prevention efforts.

Association between trajectories of prescription opioid use and risk of opioid use disorder and overdose among US nonmetastatic breast cancer survivors.

PURPOSE: To examine the association between prescription opioid use trajectories and risk of opioid use disorder (OUD) or overdose among nonmetastatic breast cancer survivors by treatment type. METHODS: This retrospective cohort study included female nonmetastatic breast cancer survivors with at least 1 opioid prescription fill in 2010-2019 Surveillance, Epidemiology and End Results linked Medicare data. Opioid mean daily morphine milligram equivalents (MME) calculated within 1.5 years after initiating active breast cancer therapy. Group-based trajectory models identified distinct opioid use trajectory patterns. Risk of time to first OUD/overdose event within 1 year after the trajectory period was calculated for distinct trajectory groups using Cox proportional hazards models. Analyses were stratified by treatment type. RESULTS: Four opioid use trajectories were identified for each treatment group. For 38,030 survivors with systemic endocrine therapy, 3 trajectories were associated with increased OUD/overdose risk compared with early discontinuation: minimal dose (< 5 MME; adjusted hazard ratio [aHR] = 1.73 [95% CI 1.43-2.09]), very low dose (5-25 MME; 2.67 [2.05-3.48]), and moderate dose (51-90 MME; 6.20 [4.69-8.19]). For 9477 survivors with adjuvant chemotherapy, low-dose opioid use was associated with higher OUD/overdose risk (aHR = 7.33 [95% CI 2.52-21.31]) compared with early discontinuation. For 3513 survivors with neoadjuvant chemotherapy, the differences in OUD/OD risks across the 4 trajectories were not significant. CONCLUSIONS: Among Medicare nonmetastatic breast cancer survivors receiving systemic endocrine therapy or adjuvant chemotherapy, compared with early discontinuation, low-dose or moderate-dose opioid use were associated with six- to sevenfold higher OUD/overdose risk. Breast cancer survivors at high-risk of OUD/overdose may benefit from targeted interventions (e.g., pain clinic referral).

Hospitalization, Overdose, and Mortality After Opioid Prescriptions Tied to Ophthalmic Surgery.

PURPOSE: Opioid prescriptions continue to carry significant short- and long-term systemic risks, even after ophthalmic surgery. The goal of this study was to identify any association of opioid prescription, after ophthalmic surgery, with postoperative hospitalization, opioid overdose, opioid dependence, and all-cause mortality. DESIGN: Retrospective, cross-sectional analysis. PARTICIPANTS: Patients undergoing an ophthalmic surgery in the OptumLabs Data Warehouse. METHODS: We used deidentified administrative claims data from the OptumLabs Data Warehouse to create 3 cohorts of patients for analysis from January 1, 2016, to June 30, 2022. The first cohort consisted of 1-to-1 propensity score-matched patients who had undergone ophthalmic surgery and had filled a prescription for an opioid and not filled a prescription for an opioid. The second cohort consisted of patients who were considered opioid naïve and had filled a prescription for an opioid matched to patients who had not filled a prescription for an opioid. The last cohort consisted of opioid-naïve patients matched across the following morphine milligram equivalents (MME) groups: ≤ 40, 41-80, and > 80. MAIN OUTCOME MEASURES: Short- and long-term risks of hospitalization, opioid overdose, opioid dependency/abuse, and death were compared between the cohorts. RESULTS: We identified 1 577 692 patients who had undergone an ophthalmic surgery, with 312 580 (20%) filling an opioid prescription. Among all patients, filling an opioid prescription after an ophthalmic surgery was associated with increased mortality (hazard rate [HR], 1.28; 95% confidence interval [CI], 1.25-1.31; P < 0.001), hospitalization (HR, 1.51; 95% CI, 1.49-1.53; P < 0.001), opioid overdose (HR, 7.31; 95% CI, 6.20-8.61, P < 0.001), and opioid dependency (HR, 13.05; 95% CI, 11.48-14.84; P < 0.001) compared with no opioid prescription. Furthermore, we found that higher MME doses of opioids were associated with higher rates of mortality, hospitalization, and abuse/dependence. CONCLUSIONS: Patients who filled an opioid prescription after an ophthalmic surgery experienced higher rates of mortality, hospitalization, episodes of opioid overdose, and opioid dependence compared with patients who did not fill an opioid prescription. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Multilevel Factors Impacting Substance Use Treatment Access, Engagement, and Racial Equity Among Opioid Overdose Survivors in Boston, MA.

BACKGROUND: There are well-documented racial/ethnic inequities in drug-related overdoses and access to evidence-based opioid use services nationally and in Boston, MA. OBJECTIVE: To qualitatively explore the drivers of racial/ethnic inequities in access to opioid use disorder treatment and services in Boston. DESIGN: Semi-structured qualitative interviews. PARTICIPANTS: Using purposive sampling, researchers recruited 59 opioid overdose survivors in Boston who self-identified as Black, Hispanic or Latino/a/x, and/or White. APPROACH: Interviewers administered a socio-demographic and drug use survey, and used a semi-structured interview guide to explore experiences with and perspectives on substance use treatment and services. KEY RESULTS: Participants' racial/ethnic identities were distributed across three subgroups: non-Hispanic Black (n = 18; 31%), non-Hispanic White (n = 18; 31%), and Latino/a/x (n = 23; 39%). Qualitative analysis identified multiple themes that were organized into four social-ecological levels after analysis. At the individual level, some participants emphasized the importance of personal responsibility and individual motivation in determining access to services. Participants expressed a range of perspectives about using medication for opioid use disorder treatment; Black and Latino/a/x participants were more likely than White participants to have critical perspectives. At the interpersonal level, experiences of bias, stigma, and racism from staff in healthcare and treatment settings were common. At the program/process level, participants described challenges connecting to services following overdose and barriers within specific programs, with Black and Latino/a/x participants experiencing particular gaps. At the systems level, the limited availability of housing, employment, and mental health care negatively impacted treatment access and engagement. CONCLUSION: A racism lens was used during data interpretation to apply the themes at a broader population level. Through this lens, the identified barriers can be understood to have a disproportionate impact on people of color. Findings call for programmatic and policy solutions that address racism, break down stigma, and ensure equitable access to evidence-based services and social supports.

Considering Adverse Effects of Common Antihypertensive Medications in the ED.

PURPOSE OF REVIEW: To evaluate the adverse effects of common antihypertensive agents utilized or encountered in the Emergency Department. RECENT FINDINGS: All categories of antihypertensive agents may manifest adverse effects, inclusive of adverse drug reactions (ADRs), drug-to-drug interactions, or accidental overdose. Adverse effects, and specifically ADRs, may be stratified into the organ systems affected, might require specific time-sensitive interventions, could pose particular risks to vulnerable populations, and may result in significant morbidity, and potential mortality. Adverse effects of common antihypertensive agents may be encountered in the ED, necessitating that ED systems of care are poised to prevent, recognize, and intervene when adverse effects arise.

Epidemiology of drug arrests in the United States: Evidence from the national survey on drug use and health, 2015-2019.

OBJECTIVE: Following changes to drug criminalization policies, we re-examine the epidemiology of drug arrests among people who use drugs (PWUD) in the U.S. METHODS: Serial cross-sectional data from the National Survey on Drug Use and Health (2015-2019) were utilized. Past-year illicit drug use (excluding cannabis) and drug arrests were described by year, area of residence, drug use characteristics and participant demographics. Adjusted associations between race and drug arrest were estimated using multivariable logistic regression. RESULTS: Past-year illicit drug use remained consistent over time and was highest among non-Hispanic (NH) white respondents. Of those reporting past-year illicit drug use (n = 25,429), prevalence of drug arrests remained stable over time overall and in metro areas while increasing in non-metro areas. Arrests were elevated among NH Black participants and those with lower income, unemployment, housing transience, non-metro area residence, polysubstance use, history of drug injection, substance use dependence and past-year drug selling. Adjusted odds of drug arrest remained significantly higher among NH Black individuals [aOR 1.92, 95% CI 1.30, 2.84]. CONCLUSION: Despite recent shifts away from punitive drug policies, we detected no reduction in drug arrests nationally and increasing prevalence in non-metro areas. Despite reporting the lowest level of illicit substance use and drug selling, NH Black individuals had significantly increased odds of arrest across years. Findings highlight the need for further examination of policy implementation and policing practices in different settings, with more research focused non-metro areas, to address enduring structural racism in drug enforcement and its consequences for health.

Reducing perceived barriers to scaling up overdose education and naloxone distribution and medications for opioid use disorder in the United States in the HEALing (Helping End Addiction Long-Term®) communities study.

BACKGROUND: Scaling up overdose education and naloxone distribution (OEND) and medications for opioid use disorder (MOUD) is needed to reduce opioid overdose deaths, but barriers are pervasive. This study examines whether the Communities That HEAL (CTH) intervention reduced perceived barriers to expanding OEND and MOUD in healthcare/behavioral health, criminal-legal, and other/non-traditional venues. METHODS: The HEALing (Helping End Addiction Long-Term®) Communities Study is a parallel, wait-list, cluster randomized trial testing the CTH intervention in 67 communities in the United States. Surveys administered to coalition members and key stakeholders measured the magnitude of perceived barriers to scaling up OEND and MOUD in November 2019-January 2020, May-June 2021, and May-June 2022. Multilevel linear mixed models compared Wave 1 (intervention) and Wave 2 (wait-list control) respondents. Interactions by rural/urban status and research site were tested. RESULTS: Wave 1 respondents reported significantly greater reductions in mean scores for three outcomes: perceived barriers to scaling up OEND in Healthcare/Behavioral Health Venues (-0.26, 95% confidence interval, CI: -0.48, -0.05, p = 0.015), OEND in Other/Non-traditional Venues (-0.53, 95% CI: - 0.84, -0.22, p = 0.001) and MOUD in Other/Non-traditional Venues (-0.34, 95% CI: -0.62, -0.05, p = 0.020). There were significant interactions by research site for perceived barriers to scaling up OEND and MOUD in Criminal-Legal Venues. There were no significant interactions by rural/urban status. DISCUSSION: The CTH Intervention reduced perceived barriers to scaling up OEND and MOUD in certain venues, with no difference in effectiveness between rural and urban communities. More research is needed to understand facilitators and barriers in different venues.

Contemporary burden and trends of opioid-overdose mortality in New York State.

BACKGROUND: Limited research exists on contemporary opioid overdose mortality burden and trends in New York State, with most studies focusing on New York City. This study aimed to assess opioid overdose burden and death trends in New York State by age, sex, race/ethnicity, geographic area, opioid type, and overdose intent from 1999 to 2020. METHODS: Mortality data were obtained from the Centers for Disease Control and Prevention's WONDER database. Opioid overdose decedents were identified using relevant International Classification of Diseases, 10th Revision codes. Joinpoint regression analyzed trends, estimating annual and average annual percentage changes in age-adjusted mortality rates (AAMR). 95% confidence intervals were derived using the Parametric Method. RESULTS: From 1999 to 2020, New York State recorded 34,109 opioid overdose deaths (AAMR = 7.9 per 100,000 persons; 95% CI: 7.8-7.9). The overall trend increased by 12.6% per year (95% CI: 10.8, 14.4) from 2004 to 2020. Subgroups exhibited varying trends, with an 11.1% yearly increase among Non-Hispanic White persons from 2007 to 2020 (95% CI: 9.0, 13.2), a 24.6% annual rise among Non-Hispanic Black persons from 2012 to 2020 (95% CI: 17.7, 31.8), and an 18.3% increase yearly among Hispanic individuals from 2011 to 2020 (95% CI: 14.0, 22.9). Recent trends have worsened in both males and females, across all age groups, in both New York City (NYC) and areas outside NYC, and for heroin, natural and semisynthetic opioids, and synthetic opioids. CONCLUSIONS: Opioid overdose mortality in New York State has worsened significantly in the last two decades. Further research is essential to identify driving factors for targeted public health interventions.

Economic Evaluations of Establishing Opioid Overdose Prevention Centers in 12 North American Cities: A Systematic Review.

OBJECTIVES: Overdose prevention centers (OPCs) provide a safe place where people can consume preobtained drugs under supervision so that a life-saving medical response can be provided quickly in the event of an overdose. OPCs are programs that are established in Canada and have recently become legally sanctioned in only a few United States jurisdictions. METHODS: We conducted a systematic review that summarizes and identifies gaps of economic evidence on establishing OPCs in North America to guide future expansion of OPCs. RESULTS: We included 16 final studies that were evaluated with the Consolidated Health Economic Evaluation Reporting Standards and Drummond checklists. Eight studies reported cost-effectiveness results (eg, cost per overdose avoided or cost per quality-adjusted life-year), with 6 also including cost-benefit; 5 reported only cost-benefit results, and 3 cost offsets. Health outcomes primarily included overdose mortality outcomes or HIV/hepatitis C virus infections averted. Most studies used mathematical modeling and projected OPC outcomes using the experience of a single facility in Vancouver, BC. CONCLUSIONS: OPCs were found to be cost-saving or to have favorable cost-effectiveness or cost-benefit ratios across all studies. Future studies should incorporate the experience of OPCs established in various settings and use a greater diversity of modeling designs.

Neighborhood and Individual Disparities in Community-Based Naloxone Access for Opioid Overdose Prevention.

Improving access to naloxone for laypersons is a cornerstone of the US strategy to reduce opioid overdose deaths. This study evaluated change in distance to opioid overdose prevention programs (OOPPs) providing walk-in naloxone across two time points. We also explored individual and neighborhood disparities in distance to OOPPs, associations between 2020 OOPP locations and 2018 overdoses, and associations between OOPPs and neighborhood fatal overdose rates. Using fatal opioid overdose locations in 2018 (n = 1167) and 2020 (n = 2045) in New York City, we mapped OOPP locations and fatal overdose locations to visualize areas of unmet naloxone need. We used logistic regression to assess individual (age, sex, race/ethnicity) and neighborhood correlates of odds of an overdose occurring within walking distance (≤ 0.5 miles or 0.8 km) of an OOPP and negative binomial regression to assess the relationship between census tract-level OOPP counts and overdose rates. Distance to OOPPs significantly improved over time, with average distance decreasing by 1.7 miles (2.7 km) (p < 0.001). OOPPs were more likely to be located in neighborhoods with higher poverty in both years and in closer proximity to Latinos in 2020-suggesting improved access for Latinos and in higher poverty neighborhoods. OOPP locations in 2020 were significantly positively associated with overdose locations in 2018. OOPPs were not well-situated in neighborhoods with elevated overdose rates in 2018 but were better situated in 2020, controlling for other neighborhood variables. Community lay naloxone access through OOPPs improved over time and could have promising effects for improved overdose rates in the future.

Overdose from Unintentional Fentanyl Use when Intending to Use a Non-opioid Substance: An Analysis of Medically Attended Opioid Overdose Events.

Fentanyl-mixed and substituted heroin is well-documented, but less is known about unintentional fentanyl use among people using stimulants. To determine the prevalence of and racial and ethnic disparities in unintentional fentanyl use among people experiencing a medically attended opioid overdose, we reviewed 448 suspected non-fatal overdose cases attended by a community paramedic overdose response team in San Francisco from June to September 2022. We applied a case definition for opioid overdose to paramedic records and abstracted data on intended substance use prior to overdose. Among events meeting case criteria with data on intended substance use, intentional opioid use was reported by 57.3%, 98.0% of whom intended to use fentanyl. No intentional opioid use was reported by 42.7%, with most intending to use stimulants (72.6%), including methamphetamine and cocaine. No intentional opioid use was reported by 58.5% of Black, 52.4% of Latinx, and 28.8% of White individuals (p = 0.021), and by 57.6% of women and 39.5% of men (p = 0.061). These findings suggest that unintentional fentanyl use among people without opioid tolerance may cause a significant proportion of opioid overdoses in San Francisco. While intentional fentanyl use might be underreported, the magnitude of self-reported unintentional use merits further investigation to confirm this phenomenon, explore mechanisms of use and disparities by race and ethnicity, and deploy targeted overdose prevention interventions.

Bridging the Gap in Harm Reduction Using Mobile Overdose Response Services (MORS) in the Context of the COVID-19 Pandemic: A Qualitative Study.

The COVID-19 pandemic introduced additional health challenges for people who use substances (PWUS) amid the overdose crisis. Numerous harm reduction services, including supervised consumption sites (SCS) across Canada, faced shutdowns and reduced operating capacity in order to comply with public health measures. Mobile Overdose Response Services (MORS) are novel overdose prevention technologies that allow those who are unable to access alternative means of harm reduction to consume substances under the virtual supervision of a trained operator. Here, we examine the role of MORS in the context of the COVID-19 pandemic. A total of 59 semi-structured interviews were conducted with the following key interest groups: PWUS, healthcare providers, harm reduction workers, MORS operators, and the general public. Inductive thematic analysis informed by grounded theory was used to identify major themes pertaining to the perception of MORS. As the pandemic shifted the public focus away from harm reduction, many participants viewed MORS as an acceptable strategy to reduce the harms associated with solitary substance and alleviate the sense of isolation driven by social distancing measures. While the pandemic may have increased the utility of MORS, concerns surrounding personal privacy and confidentiality remained. Overall, MORS were perceived as a useful adjunct service to address the unmet needs PWUS during the pandemic and beyond.

Drug Overdose Death Following Substance Use Disorder Treatment Termination in New York City: A Retrospective Longitudinal Cohort Study.

Drug overdose death rates are the highest recorded in New York City (NYC). Substance use disorder (SUD) treatment termination can confer increased risk of drug overdose death. Our objective was to determine the probability of, and factors associated with, drug overdose death following SUD treatment termination. Using a retrospective longitudinal cohort design, we identified those who had NYC-based SUD treatment terminated (01/2016-06/2019) using Chief Medical Examiner and SUD treatment data. Using survival analyses, we examined drug overdose deaths ≤ 14 and ≤ 90 days following SUD treatment termination, respectively. Of 51,171 patients with SUD treatment termination, 140 and 342 had a drug overdose death < 14 and ≤ 90 days, respectively. The crude drug overdose death rate was 26.7 per 1000 person-years at-risk in the ≤ 90-day period and was 71.6 per 1000 person-years at-risk in the ≤ 14-day period. In adjusted Cox proportional hazard model examining death ≤ 14 days, those unemployed (compared to employed) and those terminated from residential treatment (compared to medically supervised withdrawal, opioid treatment programs, and outpatient treatment) were more likely to have had a drug overdose death (all p-values < 0.01). In adjusted Cox proportional hazard model examining death ≤ 90 days, non-Hispanic White people (compared to non-Hispanic Black people), those not stably housed (compared to stably housed), those unemployed and those terminated from residential treatment were more likely to have had a drug overdose death (all p-values < 0.01). Strategies to improve retention including the reassessment of program treatment termination criteria along with strategies to promote ongoing OUD treatment, engagement in harm reduction, and distribution of naloxone are needed.

Characterizing Use of Supervised Consumption Services among Street-involved Youth and Young Adults in the Context of an Overdose Crisis.

In response to an increase in overdose deaths, there was a rapid scale-up of supervised consumption services (SCS), including federally sanctioned SCS and low-barrier SCS known as overdose prevention sites (OPS), in Vancouver, Canada, beginning in December 2016. However, little is known about the use of such services among adolescents and young adults (AYA) in this context. We therefore sought to characterize factors associated with the use of federally sanctioned SCS and OPS among street-involved AYA who inject drugs in Vancouver during an overdose crisis. From December 2016 to March 2020, data were collected from a prospective cohort of street-involved AYA aged 14 to 26 at baseline. Using multivariable generalized estimating equation analyses, we identified factors associated with recent use of federally sanctioned SCS and OPS, respectively. Among 298 AYA who inject drugs, 172 (57.8%) and 149 (50.0%) reported using federally sanctioned SCS and OPS during the study period, respectively. In multivariable analyses, public injecting, negative police interactions, and residing or spending time ≥ weekly in the Downtown Eastside neighborhood were all positively associated with the use of federally sanctioned SCS and OPS, respectively. Additionally, ≥ daily unregulated opioid use and residential eviction were positively associated with federally sanctioned SCS use, while requiring help injecting was inversely associated. Self-identified female or non-binary gender was also positively associated with OPS use (all p < 0.05). Both federally sanctioned SCS and OPS successfully engaged AYA at heightened risk of adverse health outcomes. However, the lack of accommodation of AYA who require manual assistance with injecting at federally sanctioned SCS may be inhibiting service engagement.

Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity.

INTRODUCTION: Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. METHODS: In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson's correlation analyses were performed. RESULTS: In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). CONCLUSION: This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Abnormal blood concentration changes in a 71-year-old female who survived a 10,000mg overdose of clozapine: a case report.

BACKGROUND: Clozapine is a highly effective second-generation antipsychotic with few extrapyramidal reactions, making it a preferred choice among clinicians. However, instances of acute clozapine poisoning resulting from suicide attempts and misuse have been reported. Through our review of existing literature, we identified that we believe to be the highest recorded overdose of clozapine in elderly patients, resulting in a nonfatal outcome. CASE PRESENTATION: The case report involves a 71-year-old female with a history of depression who ingested a dose of 10,000 mg of clozapine. Approximately 6 h after the overdose, the clozapine level was 5,200 µg/L, significantly surpassing the recommended therapeutic concentration range of 350-600 µg/L. After gastric lavage and hemoperfusion, the blood level dropped to 1847.11 µg/L. Notably, during therapeutic drugs monitoring (TDM), we found a perplexing spike in the patient's blood level to 5554.15 µg/L after the second hemoperfusion. CONCLUSION: In this case we mainly focused on the abnormal fluctuations in the concentration of clozapine. We conducted a comprehensive analysis of potential factors contributing to this abnormal phenomenon in terms of the patient's age, clinical symptoms, various laboratory test indexes, and the pharmacokinetics of clozapine. Our findings underscore the importance of timely TDM and the precision of results in managing elderly patients experiencing high-dose clozapine poisoning.

Simultaneous multi-targeted forensic toxicological screening in biological matrices by MRM-IDA-EPI mode.

The toxicologist ascertains drug assumptions in case of paediatric intoxications and death for overdose. The analytical approach consists of initially screening and consequently confirming drug positivity. We developed a toxicological screening method and validated its use comparing the results with a LC-MS/MS analysis. The method identifies 751 drugs and metabolites (704 in positive and 47 in negative mode). Chromatographic separation was achieved eluting mobile phase A (10 mM ammonium formate) and B (0.05% formic acid in methanol) in gradient on Kinetex Phenyl-Hexyl (50 × 4.6 mm, 2.6 µm) with 0.7 mL/min flow rate for 11 min. Multiple Reaction Monitoring (MRM) was adopted as survey scan and, after an Information-Dependent Analysis (IDA) (threshold of 30,000 for positive and 1000 cps for negative mode), the Enhanced Product Ion (scan range: 50-700 amu) was triggered. The MS/MS spectrum generated was compared with one of the libraries for identification. Data processing was optimised through creation of rules. Sample preparation, mainly consisting of deproteinization and enzymatic hydrolysis, was set up for different matrices (blood, urine, vitreous humor, synovial fluid, cadaveric tissues and larvae). Cut-off for most analytes resulted in the lowest concentration tested. When the results from the screening and LC-MS/MS analysis were compared, an optimal percentage of agreement (100%) was assessed for all matrices. Method applicability was evaluated on real paediatric intoxications and forensic cases. In conclusion, we proposed a multi-targeted, fast, sensitive and specific MRM-IDA-EPI screening having an extensive use in different toxicological fields.