Evaluation of the relationship of xylazine and fentanyl blood concentrations among fentanyl-associated fatalities.

INTRODUCTION: Illicit fentanyl and fentanyl-analogs have produced a devastating increase in opioid fatalities in the United States. Increasingly, xylazine has been found in the illicit fentanyl supply. The role of xylazine in fentanyl intoxication remains unclear. We reviewed coroner records to evaluate trends and effects associated with xylazine in fentanyl-related fatalities. METHODS: This is a retrospective cohort study of all deaths reported to the Franklin County Coroner's Office in Ohio from 1 January 2019 to 16 March 2023, in which fentanyl was determined causative or contributory to death. Cases identified as fentanyl-associated fatalities were separated into two groups based on whether or not xylazine was also detected. RESULTS: There were 3,052 fentanyl-related fatalities during the study period. 4.8 percent of these decedents also tested positive for xylazine. There was no meaningful demographic difference between fentanyl-related fatalities in which xylazine was detected versus those without xylazine detected. There was a mean of 726 fentanyl-associated fatalities per year, with a peak of 846 deaths in 2020 and a decline thereafter. The percentage of fentanyl-related fatalities with xylazine detected increased in linear fashion from 2.7 percent in 2019 to 6.6 percent in 2022. The median fentanyl concentration was 17.0 µg/L (inter-quartile range: 7.9, 27.0) in cases with xylazine detected and 10.0 µg/L (inter-quartile range: 5.6, 18.0) without xylazine. The odds of a fentanyl concentration greater than 40 µg/L in cases with xylazine detected was more than twice as great (odds ratio: 2.41; 95 percent confidence interval: 1.58-3.64) than that in cases without xylazine detected. CONCLUSIONS: Postmortem fentanyl concentrations were greater in cases with xylazine detected than those without xylazine detected. Though it is unclear why patients who were exposed to xylazine tolerated higher opioid doses prior to succumbing to death, we postulate that xylazine may act to competitively antagonize some degree of mu-opioid receptor binding by opioids.

Glucagon-Like Peptide-1 Receptor Agonist Cases Reported to United States Poison Centers, 2017-2022.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications for management of diabetes and obesity. The objective of this study is to characterize the epidemiology of GLP-1RA cases reported to US poison centers. METHODS: We analyzed cases involving a GLP-1RA reported to the National Poison Data System during 2017-2022. RESULTS: There were 5,713 single-substance exposure cases reported to US poison centers involving a GLP-1RA. Most cases were among females (71.3%) and attributable to therapeutic errors (79.9%). More than one-fifth (22.4%) of cases were evaluated in a healthcare facility, including 0.9% admitted to a critical care unit and 4.1% admitted to a non-critical care unit. Serious medical outcomes were described in 6.2% of cases, including one fatality. The rate of cases per one million US population increased from 1.16 in 2017 to 3.49 in 2021, followed by a rapid increase of 80.9% to 6.32 in 2022. Trends for rates of serious medical outcomes and admissions to a healthcare facility showed similar patterns with 129.9% and 95.8% increases, respectively, from 2021 to 2022. CONCLUSIONS: Most GLP-1RA cases reported to US poison centers were associated with no or minimal effects and did not require referral for medical treatment; however, a notable minority of individuals experienced a serious medical outcome or healthcare facility admission. The rate of reported cases increased during the study period, including an 80.9% increase from 2021 to 2022. Opportunities exist to improve provider and patient awareness of the adverse effects of these medications.

Cardiac Myosin Inhibitors: Expanding the Horizon for Hypertrophic Cardiomyopathy Management.

OBJECTIVE: To review the current literature on the efficacy and safety of cardiac myosin inhibitors (CMIs) for the treatment of hypertrophic cardiomyopathy (HCM). DATA SOURCES: A literature search was conducted on PubMed from origin to April 2023, using the search terms "MYK-461," "mavacamten," "CK-3773274," and "aficamten." Studies were limited to English-based literature, human subjects, and clinical trials resulting in the inclusion of 13 articles. ClinicalTrials.gov was also used with the same search terms for ongoing and completed trials. STUDY SELECTION AND DATA EXTRACTION: Only phase II and III studies were included in this review except for pharmacokinetic studies that were used to describe drug properties. DATA SYNTHESIS: CMIs enable cardiac muscle relaxation by decreasing the number of myosin heads that can bind to actin and form cross-bridges. Mavacamten, the first Food and Drug Administration (FDA)-approved drug in this class, has been shown to improve hemodynamic, functional, and quality of life measures in HCM with obstruction. In addition, aficamten is likely to become the next FDA-approved CMI with promising phase II data and an ongoing phase III trial expected to release results in the next year. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: CMIs provide a novel option for obstructive hypertrophic cardiomyopathy, particularly in those not suitable for septal reduction therapy. Utilization of these agents requires knowledge of drug interactions, dose titration schemes, and monitoring parameters for safety and efficacy. CONCLUSIONS: CMIs represent a new class of disease-specific drugs for treatment of HCM. Cost-effectiveness studies are needed to delineate the role of these agents in patient therapy.

Loperamide cases reported to United States poison centers, 2010-2022.

BACKGROUND: Intentional use of high doses of loperamide has been linked to serious cardiac toxicity. The objective of this study is to investigate the characteristics and trends of loperamide cases reported to United States (US) poison centers and to evaluate the changes in reported loperamide cases following US Food and Drug Administration (FDA) warnings, labeling requirements, and packaging restrictions for loperamide starting in 2016, with an emphasis on intentional exposures. METHODS: Data from the National Poison Data System were analyzed. RESULTS: There were 12,987 cases reported to US poison centers from 2010 to 2022, for which, loperamide was the most likely substance responsible for observed clinical effects. Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%). Eight percent (8.1%) of cases were admitted to a critical care unit and 5.0% were admitted to a non-critical care unit. Among cases with a serious medical outcome, most were associated with loperamide abuse (38.0%), intentional-misuse (15.7%), or suspected suicide (27.5%). The majority (60.0%; n = 33) of fatalities were related to abuse, followed by suspected suicide (20.0%; n = 11) and intentional-misuse (5.5%, n = 3). The rate of loperamide cases per 100,000 US population reported to US PCs decreased from 0.44 in 2010 to 0.36 in 2015 (p = 0.0290), followed by an increase to 0.46 in 2017 (p = 0.0013), and then a trend reversal with a decrease to 0.28 in 2022 (p < 0.0001). The rate of serious medical outcomes related to loperamide increased from 0.03 in 2010 to 0.05 in 2015 (p = 0.0109), which subsequently increased rapidly to 0.11 in 2017 (p < 0.0001), and then demonstrated a trend reversal and decreased to 0.04 in 2022 (p < 0.0001). CONCLUSIONS: FDA warnings, labeling requirements, and packaging restrictions may have contributed to the observed trend reversal and decrease in reports to US poison centers of loperamide cases related to intentional misuse, abuse, and suspected suicide. This demonstrates the potential positive effect that regulatory actions may have on public health. These findings contribute to the evidence supporting the application of similar prevention efforts to reduce poisoning from other medications associated with intentional misuse, abuse, and suicide.

Hydrocarbon ingestions among individuals younger than 20 years old reported to United States Poison Centers, 2000-2021.

BACKGROUND: Hydrocarbon-based products have many household and commercial uses and exposure to these substances is common. Severe clinical effects can occur if these products are ingested. This study investigated the characteristics and trends of hydrocarbon ingestions reported to United States Poison Centers. METHODS: Data from the National Poison Data System were analyzed for cases of hydrocarbon ingestion among individuals < 20 years old reported to United States Poison Centers from January 1, 2000 through December 31, 2021. RESULTS: There were 284,085 hydrocarbon ingestions reported during the 22-year study period in which a hydrocarbon was the first-ranked substance. Most of these cases occurred among children < 6 years old (83.2%), males (64.6%), at a residence (96.5%), were single-substance exposures (98.3%), and were managed on-site rather than in a health care facility (74.9%). However, 4.5% of cases were associated with a serious medical outcome, including 34 deaths. Thirty-two deaths were among children < 6 years old and most were associated with aspiration. Gasolines accounted for 24.6% of total cases, followed by lubricating oils and/or motor oils (19.9%), other types of hydrocarbons (14.9%), lamp oils (11.3%), and lighter fluids and/or naphtha (10.3%). The rate of hydrocarbon ingestions among United States youth < 20 years old decreased significantly (p < 0.0001) by 66.5% from 2000 to 2021. The greatest rate decrease was observed among lamp oils (- 78.4%, p < 0.0001), followed by gasolines (- 75.9%, p < 0.0001). CONCLUSIONS: Although the rate of hydrocarbon ingestions decreased during the study period and most reported cases resulted in non-serious outcomes, the number of cases remains high with a non-trivial minority (4.5%) of cases associated with a serious medical outcome, including death. Most deaths were among children < 6 years old. This underscores the need to increase primary prevention efforts, especially for young children.

Pediatric ADHD Medication Errors Reported to United States Poison Centers, 2000 to 2021.

OBJECTIVES: To investigate the characteristics and trends of out-of-hospital attention-deficit/hyperactivity disorder (ADHD) medication-related therapeutic errors among youth <20 years old reported to US poison centers. METHODS: National Poison Data System data from 2000 through 2021 were analyzed. Population-based rates were calculated using US census data. RESULTS: There were 124 383 ADHD medication-related therapeutic errors reported to US poison centers from 2000 through 2021, with the annual frequency increasing by 299.0% during that period. Two-thirds (66.6%) of the 87 691 first-ranked exposures involved children 6 to 12 years old, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were single-substance exposures. Although most (82.7%) individuals did not receive treatment in a health care facility (HCF), 2.3% were admitted to a HCF and 4.2% had a serious medical outcome. Children <6 years old were more likely to experience a serious medical outcome (odds ratio = 2.1; 95% confidence interval: 1.9-2.3) or be admitted to a HCF (odds ratio = 3.4; 95% confidence interval: 3.0-3.7) than 6 to 19-year-olds. The most common scenarios were "inadvertently taken or given medication twice" (53.9%), followed by "inadvertently taken or given someone else's medication" (13.4%), and "wrong medication taken or given" (12.9%). CONCLUSIONS: The frequency of cases reported to poison centers of pediatric out-of-hospital therapeutic errors related to ADHD medications increased by almost 300% during the 22-year study period and is likely attributable to increased prescribing of these medications. Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems.