Search

This article describes the results of a literature search of pertinent professional literature written on issues important to rural healthcare delivery in the United States. The purpose of the literature review was to provide journal articles to practicing rural healthcare leaders who, because of time and economic constraints, claimed they were unable to research their own relevant journal articles. The authoring team is composed of individuals who work as full-time faculty members at institutions that offer courses in health administration. Because the nature of their professional work and research dictates that they focus on areas of rural health, the authoring team offered to share their findings with rural administrators as a means to assist them. The intent was to form a working collaboration between health services management professionals in academia, representatives of the state's healthcare organizational affiliate associations, and professionals practicing in the industry. This ten-year collaboration resulted in a unique wedding of resources that helped both in the delivery of rural healthcare services in a western state and in the advancement of the field of health services administration through original research. Thus, the product of this literature search is a comprehensive study of the trends in rural healthcare delivery. The variety of topics discussed were gleaned from over 500 articles found in and summarized from 70 professional healthcare journals published between 1990 and 1999. [ABSTRACT FROM AUTHOR]

Women with urinary urgency and frequency may also have pelvic floor muscle spasm. Transvaginal biofeedback (TVBF) and electrical stimulation (EStim) is a treatment modality that has been used to treat vaginismus and chronic pelvic pain. In this study, TVBF/EStim was evaluated in women with pelvic floor muscle spasm associated with urinary symptoms. Fifty-two women underwent therapy with TVBF/EStim and reported a mean symptom improvement of 64.5%. [ABSTRACT FROM AUTHOR]

Background: Testicular ischemia requires timely diagnosis and definitive management to avoid serious consequences such as orchiectomy. It is almost always caused by testicular torsion; however, there are other causes to be aware of., Case Report: A 32-year-old man developed testicular ischemia following a laparoscopic robotic-assisted inguinal hernia repair with preperitoneal mesh. The ischemia progressed to a fully infarcted testicle with no evidence of torsion on subsequent surgical exploration. He ultimately did require an orchiectomy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: While extremely rare, testicular ischemia or infarct must be considered in patients presenting with testicular pain shortly after inguinal hernia repair. Emergent surgical evaluation and loosening of the hernia mesh may be required to salvage the testicle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The views expressed in this material are those of the authors and do not reflect the official policy or position of the U.S. Government, the Department of Defense, or the Departments of the Army or Air Force., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species, the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole-body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [ 14 C]LEN in intravenously dosed bile duct-cannulated rats and dogs showed a substantial amount of unchanged LEN (31%-60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was < 1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in H μ rel hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT: LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates., (Copyright © 2024 by The Author(s).)

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC ( n = 121 donors) and HH ( n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age 50 ) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly ( R 2 = 0.95; p < 0.0001) in samples showing <10% contribution of glucuronidation toward the overall metabolism, confirming that AO-mediated oxidation and glucuronidation are the key routes of carbazeran metabolism. Considering the confounding effect of glucuronidation on AO activity, AO content-based ontogeny data are a more direct reflection of developmental changes in protein expression. The comprehensive ontogeny data of AO in HH samples are more reliable than HLC data, which are important for developing robust physiologically based pharmacokinetic models for predicting AO-mediated metabolism in children.

The opioid public health crisis continues to burden individuals, communities, and economies. Public health opinion has emphasized the need for increased access to harm reduction services, but there is a dearth of information on the views and experiences of people who use opioids. Our study aimed to investigate the prevalence of naloxone use, attitudes, and experiences with naloxone among an online community of people who use drugs. We performed a cross-sectional survey looking at experiences with and attitudes towards take-home naloxone. Data is presented descriptively, with analysis of the differences between people who do and do not use opioids using the χ 2 and Fisher's exact tests. There were 1,143 respondents, of whom 70% were from the United States. Only 38% of participants who use opioids had received naloxone training, but 56% of these individuals said that they felt comfortable using a naloxone kit. Nearly all respondents (95%) said they would be willing to use naloxone on someone who had overdosed and approximately 90% would want naloxone used on them in case of an overdose. Regarding harm reduction, 24% of respondents said they had access to safe use programs, and 33% said they had access to clean needle exchange programs. A majority of the participants who use opioids were in favor of having naloxone with them when using drugs and believed naloxone should be freely available. This study demonstrates the receptiveness of take-home naloxone and highlights the need for better implementation of naloxone within communities that use opioids., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Military medical personnel are crucial in providing life-saving care at the point of injury (POI) in challenging environments such as combat zones and disaster areas. This article examines the specialized training US Military medical personnel undergo before deployment and the increasing trend of deploying as part of multinational forces in operations like those in Afghanistan with NATO and non-NATO countries. Integrating medical teams from diverse backgrounds poses significant challenges in maintaining a cohesive and efficient team due to varying trauma management training standards and medical practices among the allied forces. Tactical Combat Casualty Care (TCCC) training and the development of clinical practice guidelines (CPG) by the US Joint Trauma Service have been key strategies by the US Military to standardize care. However, the variation in trauma management training among NATO allies and the differences in medical subspecialties and approaches can lead to inefficiencies and reduced effectiveness in a multinational trauma center setting. For instance, the approach to trauma care can significantly differ between the US and European countries, impacting the interoperability and teamwork in multinational medical teams. To address these challenges, the article highlights the importance of standardized medical training programs that include cultural awareness to enhance the effectiveness of multidisciplinary, multinational medical teams. It also underscores the necessity for standardized international trauma training in the face of increasing global conflicts and the potential for large-scale combat operations. The article discusses the "Trauma Tuesday" program implemented in Kabul, Afghanistan, as an example of how intensive training and simulation exercises can improve team dynamics, knowledge, and skills in trauma management among a diverse team from various nations. The need for ongoing education and developing a standard for managing trauma patients in international teams is emphasized to ensure effective communication and coordination. The article suggests that multinational trauma training can significantly improve team cohesion and critical life-saving skills, essential for future battlefields where access to definitive care may be delayed. Further research is recommended to explore the best methods for achieving effective multinational medical team integration and training standardization., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Rifampicin (RIF) is a mixed-mode perpetrator that produces pleiotropic effects on liver cytochrome P450 enzymes and drug transporters. To assess the complex drug-drug interaction liabilities of RIF in vivo, a known probe substrate, midazolam (MDZ), along with multiple endogenous biomarkers were simultaneously monitored in beagle dogs before and after a 7-day treatment period by RIF at 20 mg/kg per day. Confirmed by the reduced MDZ plasma exposure and elevated 4 β -hydroxycholesterol (4 β -HC, biomarker of CYP3A activities) level, CYP3A was significantly induced after repeated RIF doses, and such induction persisted for 3 days after cessation of the RIF administration. On the other hand, increased plasma levels of coproporphyrin (CP)-I and III [biomarkers of organic anion transporting polypeptides 1b (Oatp1b) activities] were observed after the first dose of RIF. Plasma CPs started to decline as RIF exposure decreased, and they returned to baseline 3 days after cessation of the RIF administration. The data suggested the acute (inhibitory) and chronic (inductive) effects of RIF on Oatp1b and CYP3A enzymes, respectively, and a 3-day washout period is deemed adequate to remove superimposed Oatp1b inhibition from CYP3A induction. In addition, apparent self-induction of RIF was observed as its terminal half-life was significantly altered after multiple doses. Overall, our investigation illustrated the need for appropriate timing of modulator dosing to differentiate between transporter inhibition and enzyme induction. As further indicated by the CP data, induction of Oatp1b activities was not likely after repeated RIF administration. SIGNIFICANCE STATEMENT: This investigation demonstrated the utility of endogenous biomarkers towards complex drug-drug interactions by rifampicin (RIF) and successfully determined the optimal timing to differentiate between transporter inhibition and enzyme induction. Based on experimental evidence, Oatp1b induction following repeated RIF administration was unlikely, and apparent self-induction of RIF elimination was observed., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Physiologic and psychological effects of substance use are common occurrences. They may be the proximate purpose of the exposure or related to an unintended complication. Acute short-term exposure effects may not be the same as long-term effects. These effects are mediated by different receptors they act on and the homeostatic changes that occur due to repeat exposure. We review in this article the physiologic and psychological effects from exposure to commonly encountered drugs, ethanol, sedative hypnotics, cocaine, amphetamines, marijuana, opioids, nicotine, hydrocarbons (halogenated and non-halogenated), and nitrous oxide., (Published by Elsevier Inc.)

Substance use disorder is a growing public health challenge in the United States. People who use drugs may be more vulnerable to ambient heat due to the effects of drugs on thermoregulation and their risk environment. There have been limited population-based studies of ambient temperature and drug-related morbidity. We examined short-term associations between daily ambient temperature and emergency department (ED) visits for use or overdose of amphetamine, cocaine and opioids in California during the period 2005 to 2019. Daily ZIP code-level maximum, mean, and minimum temperature exposures were derived from 1-km data Daymet products. A time-stratified case-crossover design was used to estimate cumulative non-linear associations of daily temperature for lag days 0 to 3. Stratified analyses by patient sex, race, and ethnicity were also conducted. The study included over 3.4 million drug-related ED visits. We found positive associations between daily temperature and ED visits for all outcomes examined. An increase in daily mean temperature from the 50th to the 95th percentile was associated with ED visits for amphetamine use (OR = 1.072, 95% CI: 1.058, 1.086), cocaine use (OR = 1.044, 95% CI: 1.021, 1.068 and opioid use (OR = 1.041, 95% CI: 1.025, 1.057). Stronger positive associations were also observed for overdose: amphetamine overdose (OR = 1.150, 95% CI: 1.085, 1.218), cocaine overdose (OR = 1.159, 95% CI: 1.053, 1.276), and opioid overdose (OR = 1.079, 95% CI: 1.054, 1.106). In summary, people who use stimulants and opioids may be a subpopulation sensitive to short-term higher ambient temperature. Mitigating heat exposure can be considered in harm reduction strategies in response to the substance use epidemic and global climate change., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings., Procedures: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies., Results: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly., Conclusions: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hydrofluoric acid (HF) is associated with systemic toxicity, particularly with high-concentration formulations. However, most existing data describe dermal exposures; there is a paucity of data related to outcomes after ingestions., Objective: To determine the morbidity and mortality associated with HF ingestions as reported to the National Poison Data System (NPDS). A secondary objective is to assess for clinical criteria that are associated with serious outcomes after HF ingestion., Methods: We performed a retrospective review of HF ingestions reported to the NPDS from 2007 to 2017. Data including patient demographics, exposure and caller sites, electrolyte abnormalities, treatments, and serious (moderate or major effect or death as documented in NPDS) and non-serious outcomes were abstracted from case narratives. Cases meeting the criteria for a qualifiable HF ingestion were included in the study., Results: During the study period, there were 653 HF ingestions reported to NPDS, of which 142 were included in the final data analysis. Most HF exposures occurred in men (68.3%), and the most common exposure site was at the exposed individual's own residence (78.2%). Nearly half of all exposures (46.5%) were due to transfer into a non-labeled secondary storage container. Total of 45.8% of the cases resulted in a serious outcome. Electrolyte disturbances were associated with an increased risk of a serious outcome. Hypocalcemia was the most frequently reported electrolyte abnormality, occurring in 24.6% of cases. Nine (6.3%) individuals died., Conclusions: Mortality after HF ingestion is low. However, a large cohort of exposures occurred after the transfer of HF to secondary containers. Targeted interventions to reduce this practice are necessary to decrease hazardous chemical exposures., Competing Interests: The authors have no conflicts of interest to report., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and activity in human liver cytosol (HLC) and five recombinant human AO preparations (rAO) were determined using targeted proteomics and carbazeran oxidation assay, respectively. AO content was highly variable as indicated by the relative expression factor (REF; i.e., HLC to rAO content) ranging from 0.001 to 1.7 across different in vitro systems. The activity of AO in HLC degrades at a 10-fold higher rate in the presence of the substrate as compared with the activity performed after preincubation without substrate. To scale the metabolic activity from rAO to HLC, a protein-normalized activity factor (pnAF) was proposed wherein the activity was corrected by AO content, which revealed up to sixfold higher AO activity in HLC versus rAO systems. A similar value of pnAF was observed for another substrate, ripasudil. Physiologically based pharmacokinetic (PBPK) modeling revealed a significant additional clearance (CL; 66%), which allowed for the successful prediction of in vivo CL of four other substrates, i.e., O-benzyl guanine, BIBX1382, zaleplon, and zoniporide. For carbazeran, the metabolite identification study showed that the direct glucuronidation may be contributing to around 12% elimination. Taken together, this study identified differential protein content, instability of in vitro activity, role of additional AO clearance, and unaccounted metabolic pathways as plausible reasons for the underprediction of AO-mediated drug metabolism. Consideration of these factors and integration of REF and pnAF in PBPK models will allow better prediction of AO metabolism. SIGNIFICANCE STATEMENT: This study elucidated the plausible reasons for the underprediction of aldehyde oxidase (AO)-mediated drug metabolism and provided recommendations to address them. It demonstrated that integrating protein content and activity differences and accounting for the loss of AO activity, as well as consideration of extrahepatic clearance and additional pathways, would improve the in vitro to in vivo extrapolation of AO-mediated drug metabolism using physiologically based pharmacokinetic modeling., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Hyperkalemia is a common electrolyte abnormality with characteristic electrocardiogram changes. Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase the risk of developing hyperkalemia. This case highlights a rare life-threatening episode of hyperkalemia in an individual whose only risk factor was an ARB. A 58-year-old female presented with sudden-onset chest pressure, light-headedness, and diaphoresis. Her initial electrocardiogram showed a nearly sinusoidal rhythm with a widened ventricular depolarization (QRS) and prolonged QT-interval (QTc). Life-threatening hyperkalemia of 9.1 mmol/L was confirmed with a rapid point-of-care electrolyte panel. She was rapidly treated with calcium, potassium-shifting and eliminating medications, and emergent hemodialysis. After stabilization, a thorough workup found that the patient's only risk factor for hyperkalemia was her use of an ARB. While both ARBs and ACEIs are commonly associated with mild hyperkalemia, life-threatening hyperkalemia is rare, particularly in patients without concomitant renal failure, diabetes mellitus, adrenal disease, or potassium-sparing diuretic use. However, this case illustrates that life-threatening hyperkalemia is possible in patients solely taking an ARB without prior significant risk factors. Despite normal renal function in an individual without heart failure or diabetes, this patient developed life-threatening hyperkalemia., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Historically, the first step in treating cyanide (CN - ) toxicity utilized antidotes to induce methemoglobinemia. This is concerning in patients who are already hypoxemic or have elevated carboxyhemoglobin. Hydroxocobalamin (OHCbl) is now the first-line antidote for CN - toxicity and is not known to induce methemoglobinemia. We observed elevated methemoglobin (MetHb) levels in several patients treated with OHCbl and sought to investigate the incidence of MetHb formation following administration of OHCbl., Methods: Chart review: A single-center, retrospective case series of patients who received 5 or 10 g of hydroxocobalamin from 01/01/2011 through 04/30/2019. Data was analyzed using descriptive statistics. In-vitro study: Discarded blood was separated into whole blood and plasma samples. OHCbl and normal saline was added to reach 0×, 1×, 2×, and 4× peak therapeutic concentrations and analyzed at times 0, 2, and 4 h after administration., Results: Chart review : Twenty-seven cases of OHCbl administration were identified. The median age was 53 years (IQR 38 - 64) and 20 (74.1%) were male. Exposure to a house fire or smoke inhalation was the reason for OHCbl administration in 21 (77.8%) patients. Five (18.5%) patients received 10 g of OHCbl while the rest received 5 g. Six (22.2%) patients developed methemoglobinemia, all after 5 g OHCbl administration; four had been exposed to fire and smoke, two received the medication for severe acidosis of unknown etiology not related to fire or smoke. The median peak level was 7.1% (IQR 2.2 - 16.4%) at a median time of 11.4 h post-administration. Two patients received methylene blue (MB), neither responded. Death occurred in 17 (63%) cases. In-vitro study: We observed a dose dependent elevation in total hemoglobin but did not detect any increase in MetHb., Conclusion: We observed a noteworthy temporal association between the formation of methemoglobinemia and the administration of hydroxocobalamin. This does not appear to be an artifact of the CO-oximeters. This could have profound implications for patients who are already hypoxemic or have impaired oxygen carrying capacity from carboxyhemoglobin.

Initial reports described a hypercoagulable state and an increased risk of thrombosis in patients who tested positive for SARS-CoV-2. Infected patients with severe acute respiratory distress syndrome in the setting of coronavirus disease 2019 (COVID-19) may require extracorporeal membrane oxygenation (ECMO), leading to coagulopathies and further increasing the risk for bleeding and thrombosis. We conducted a single-center retrospective cohort study to compare the incidence of major bleeding and thrombosis in COVID-19 versus influenza-positive patients requiring ECMO. There was no difference in the incidence of major bleeding (67.7% vs. 85.7%, p = 0.287) or major thrombosis (9.7% vs. 21.4%, p = 0.356) between COVID-19 and influenza patients, respectively. COVID-19 patients experienced significantly fewer major bleeding events per ECMO days compared with influenza (0.1 [interquartile range 0-0.2] vs. 0.2 [interquartile range 0.1-0.5], p = 0.026). Influenza patients may be at higher risk for developing coagulopathies that contribute to bleeding. Larger evaluations are needed to confirm these results and further assess bleeding and thrombosis risk in these populations., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

The use of animal pharmacokinetic models as surrogates for humans relies on the assumption that the drug disposition mechanisms are similar between preclinical species and humans. However, significant cross-species differences exist in the tissue distribution and protein abundance of drug-metabolizing enzymes (DMEs) and transporters. We quantified non-cytochrome P450 (non-CYP) DMEs across commonly used preclinical species (cynomolgus and rhesus monkeys, beagle dog, Sprague Dawley and Wistar Han rats, and CD1 mouse) and compared these data with previously obtained human data. Aldehyde oxidase was abundant in humans and monkeys while poorly expressed in rodents, and not expressed in dogs. Carboxylesterase (CES) 1 abundance was highest in the liver while CES2 was primarily expressed in the intestine in all species with notable species differences. For example, hepatic CES1 was 3× higher in humans than in monkeys, but hepatic CES2 was 3-5× higher in monkeys than in humans. Hepatic UDP-glucuronosyltransferase (UGT) 1A2 abundance was ∼4× higher in dogs compared with rats, whereas UGT1A3 abundance was 3-5× higher in dog livers than its ortholog in human and monkey livers. UGT1A6 abundance was 5-6× higher in human livers compared with monkey and dog livers. Hepatic sulfotransferase 1B1 abundance was 5-7× higher in rats compared with the rest of the species. These quantitative non-CYP proteomics data can be used to explain unique toxicological profiles across species and can be integrated into physiologically based pharmacokinetic models for the mechanistic explanation of pharmacokinetics and tissue distribution of xenobiotics in animal species. SIGNIFICANCE STATEMENT: We characterized the quantitative differences in non-cytochrome P450 (non-CYP) drug-metabolizing enzymes across commonly used preclinical species (cynomolgus and rhesus monkeys, beagle dogs, Sprague Dawley and Wistar Han rats, and CD1 mice) and compared these data with previously obtained human data. Unique differences in non-CYP enzymes across species were observed, which can be used to explain significant pharmacokinetic and toxicokinetic differences between experimental animals and humans., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Bupropion is an aminoketone antidepressant. A major concern in bupropion toxicity is seizure activity, which can occur up to 24 h from ingestion. It is difficult to predict which patients will have seizures. The purpose of this study is to identify clinical features associate with seizure after bupropion overdose., Methods: We searched the Toxicology Investigators Consortium registry for a cases of poisoning by bupropion between January 1, 2014 and January 1, 2017 in patients aged 13-65. Demographic variables and clinical features were compared between patients who did and did not experience a seizure and presented as unadjusted odds ratios (OR). Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) between clinical features and seizures., Results: There were 256 cases of bupropion overdose remaining after inclusion/exclusion criteria were applied. Clinical features associated with seizure were QTc >500 (OR = 3.4, 95% CI: 1.3-8.8, p  = 0.012), tachycardia ( p  > 140) (OR = 1.9, 95% CI: 1-3.561, p  = 0.05), and age 13-18 years (2.4, 95% CI: 1.3-4.3, p  = 0.005). The mean QTc value for patients experiencing a seizure was 482 ms ( N  = 95 IQR: 59 ms) versus 454 ms ( N  = 103, IQR: 43) in patients who did not experience seizure, however, it was not possible to identify a QTc cutoff with sensitivity or specificity to predict seizures., Conclusion: Based on our analysis of data from the ToxIC registry, age (13-18), tachycardia ( p  > 140) and QTc >500 ms are associated with seizures in bupropion overdose; however, a specific QTc value may not be a useful predictor of seizures.

Remdesivir (RDV; GS-5734, Veklury), the first FDA-approved antiviral to treat COVID-19, is a single-diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which, in turn, acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (i) bioinformatic analysis of nucleoside/nucleotide metabolic enzyme mRNA expression using public human tissue and lung single-cell bulk mRNA sequence (RNA-seq) data sets, (ii) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells, (iii) biochemical studies on the catalytic rate of key enzymes, (iv) effects of specific enzyme inhibitors on the GS-443902 formation, and (v) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate MetX, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19 but also enable efficient intracellular metabolism of RDV and its MetX to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.

Background: Transfer of xenobiotics from their original container to an unlabeled or secondary container is a well-identified risk factor for poisoning. Nonetheless, recent large-scale data on the practice are unavailable. The objective of this study is to describe the incidence and features of poisonings in the United States due to xenobiotics stored in a secondary container., Methods: This was a retrospective review of the National Poison Data System (NPDS) from 2007 to 2017. Non-suicidal exposures associated with the scenario "container transfer involved (product transferred from original container to unlabeled container, incorrectly labeled container, or food container for use or storage and patient accessed product from second container)" were included., Results: Forty-five thousand five hundred and twelve cases were included. The median age of subjects was 30 years (interquartile range: 6-53); 52% were female. Cleaning products (38.2%), disinfectants (17.3%), and hydrocarbons (5.0%) were the most common xenobiotics reported. The annual incidence of cases increased over the study period. There were 9369 (20.6%) ED visits and 1856 (4.1%) hospital admissions. Most cases (72%) were deemed nontoxic or resulted in no effects; 4.4% resulted in serious outcomes (moderate effects, major effects, or death), including 23 deaths. Morbidity was highest for pesticides, prescription medications, and herbicides, with 10.3%, 9.8%, and 7.6% of cases resulting in serious outcomes, respectively. Hydrofluoric acid and herbicides were associated with the most deaths (13/23 [57%])., Conclusions: Transfer of xenobiotics to a secondary container is a scenario increasingly reported to U.S. poison centers. Although most exposures do not result in significant toxicity, ED visits are common and substantial morbidity can occur. This represents an opportunity for public health intervention to curb the practice.

Introduction: Large scale radiologic and nuclear disasters are rare; however, recent events such as the Fukushima Daiichi nuclear reactor emergency in Japan and current global political tensions have highlighted the need for health-care providers with expertise in managing radiation injuries. Medical Toxicologists have the ability to collaborate with other specialists in filling this critical role., Methods: We conducted a cross-sectional survey to assess the attitudes, experiences, and knowledge of medical toxicologists through the assistance of the American College of Medical Toxicology., Results: The survey was completed by 114 medical toxicologists during the enrollment period. Medical toxicologists who had a willingness to participate in radiologic or nuclear emergencies or who had taken care of patients contaminated with radioactive material were more likely to perform well on the knowledge assessment., Conclusion: We identified that there is a group of medical toxicologists who have the willingness, experience, and knowledge to help manage patients in the event of a radiologic or nuclear emergency.

Background: Bupropion is not known to have direct serotonin agonism or inhibit serotonin reuptake. In spite of this, it has been implicated as a causative agent of serotonin syndrome. We highlight two cases of single-agent bupropion overdose that subsequently met the diagnosis of serotonin syndrome by the Hunter criteria, despite the absence of direct serotonergic agents. CASE 1: A 14-year-old boy intentionally ingested an estimated 30 bupropion 75-mg immediate-release tablets. He presented in status epilepticus, was intubated, and was placed on midazolam and fentanyl infusions. He developed tremor, ankle clonus, and agitation. He was administered cyproheptadine for presumed serotonin syndrome with temporal improvement in his symptoms. CASE 2: A 19-year-old woman intentionally ingested an estimated 53 bupropion 150-mg extended-release tablets. She had a seizure and required sedation and intubation. During her course, she developed hyperthermia, inducible clonus, and hyperreflexia. She was treated with cyproheptadine without temporal improvement of symptoms but improved the following day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although bupropion is not known to be directly serotonergic, it has been implicated as the single causative agent after overdose. This may be due to an indirect increase in activity of serotonergic cells. In these cases, bupropion overdose resulted in a clinical presentation consistent with serotonin syndrome, with the first having a temporal improvement after treatment with cyproheptadine. Physicians need to be aware of the potential serotonergic activity of bupropion for accurate assessment and treatment of this dangerous condition., (Published by Elsevier Inc.)

Purpose: Obtaining an accurate medication history from patients on hospital admission is a priority in pharmacy practice. Timely and accurate histories are imperative as they may help determine the etiology of illness and prevent medication errors. We conducted a quality improvement project to assess the accuracy of alternate-source medication histories obtained for critically ill patients who were delirious or mechanically ventilated at the time of intensive care unit admission., Methods: Included patients were 18 years of age or older, admitted to the medical intensive care unit from August 2017 through January 2018, and had a medication history obtained from a family member or outpatient pharmacy due to active delirium or mechanical ventilation. Patients were directly interviewed after resolution of delirium or extubation. Discrepancies between the initial and follow-up histories were documented and categorized using the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Index for Categorizing Medication Errors., Results: Forty patients were included. One hundred four discrepancies were documented, with a median of 2 discrepancies per patient. The most common types of discrepancies were addition (51.9%), followed by omission (24.0%). NCC MERP index category A (51%) was the most common error classification identified., Conclusion: Discrepancies between initial and follow-up medication histories occurred at a frequent rate in delirious or mechanically ventilated patients; however, these discrepancies tended to be of low risk severity., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: B cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN., Methods: Lanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells., Results: In human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen., Conclusions: Lanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

Background: Cyanide (CN) toxicity commonly occurs during enclosed-space fires. Historically, the first step in treating CN toxicity utilized amyl nitrite and sodium nitrite to induce methemoglobinemia, which can be dangerous in this population. Hydroxocobalamin (OHCob), which binds to CN to form the nontoxic metabolite cyanocobalamin, is now the first-line antidote for CN toxicity, and has the advantage of not inducing methemoglobinemia., Case Report: A 62-year-old man presented to the Emergency Department (ED) after a house fire. He was intubated for respiratory distress and hypoxia with an initial carboxyhemoglobin of 1.3%, methemoglobin 0.3%, and anion gap 19. Eleven hours after presentation, his serum lactic acid was 9 mmol/L. Given his continued deterioration, 14 h after arrival he received OHCob 5 g i.v. for presumed CN toxicity. Methemoglobin concentration 4 min prior to OHCob administration was 0.7%, and 2 h after administration was 4.2%. This subsequently increased to 14.3% (16 h after OHCob administration) and peaked at 16.3% (47 h after OHCob administration), at which time he was administered a dose of methylene blue 50 mg i.v., 60 h after ED arrival. His methemoglobin concentrations fluctuated until a consistent downward trend starting at 92 h from ED arrival. He continued to deteriorate and expired on hospital day 5 with a methemoglobin concentration of approximately 6.0%. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: CN toxicity requires immediate recognition and treatment. The antidote, OHCob, is believed to not induce methemoglobinemia. However, this potential side effect must be considered by emergency physicians when treating suspected CN toxicity, especially if the patient does not improve after antidotal therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Current challenges in accurately predicting intestinal metabolism arise from the complex nature of the intestine, leading to limited applicability of available in vitro tools as well as knowledge deficits in intestinal physiology, including enzyme abundance. In particular, information on regional enzyme abundance along the small intestine is lacking, especially for non-cytochrome P450 enzymes such as carboxylesterases (CESs), UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs). We used cryopreserved human intestinal mucosa samples from nine donors as an in vitro surrogate model for the small intestine and performed liquid chromatography tandem mass spectrometry-based quantitative proteomics for 17 non-cytochrome P450 enzymes using stable isotope-labeled peptides. Relative protein quantification was done by normalization with enterocyte marker proteins, i.e., villin-1, sucrase isomaltase, and fatty acid binding protein 2, and absolute protein quantification is reported as picomoles per milligram of protein. Activity assays in glucuronidations and sequential metabolisms were conducted to validate the proteomics findings. Relative or absolute quantifications are reported for CES1, CES2, five UGTs, and four SULTs along the small intestine: duodenum, jejunum, and ileum for six donors and in 10 segments along the entire small intestine (A-J) for three donors. Relative quantification using marker proteins may be beneficial in further controlling for technical variabilities. Absolute quantification data will allow for scaling factor generation and in vivo extrapolation of intestinal clearance using physiologically based pharmacokinetic modeling. SIGNIFICANCE STATEMENT: Current knowledge gaps exist in intestinal protein abundance of non-cytochrome P450 enzymes. Here, we employ quantitative proteomics to measure non-cytochrome P450 enzymes along the human small intestine in nine donors using cryopreserved human intestinal mucosa samples. Absolute and relative abundances reported here will allow better scaling of intestinal clearance., Competing Interests: Conflicts of interest: CHIM is a commercial product of In Vitro ADMET Laboratories Inc., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Despite significant efforts, deaths due to drug overdose remain at near record levels. In efforts combat this crisis, the Joint Commission now requires that accredited hospitals implement safe opioid prescribing practices. Emergency department visits and hospitalizations related to opioid use disorder (OUD) provide an opportunity to initiate evidence-based treatment. However, both situations require the presence of qualified physician leaders and clinicians, which many facilities lack. Medical toxicologists have the expertise needed to fill these voids, but the scope and prevalence of their involvement are unknown. We sought to determine the engagement of medical toxicologists in leading opioid stewardship initiatives and the treatment of patients with OUD., Methods: Members of the American College of Medical Toxicology (ACMT) were surveyed about their leadership roles in opioid stewardship and clinical practices regarding OUD from March-June 2019. ACMT represents more than 80% of the nation's board-certified medical toxicologists. The electronic survey utilized branching logic and results are presented descriptively; thus, responses are presented as a percentage of the number of respondents to individual questions rather than the total number of participants., Results: One hundred and thirty-one out of 382 eligible individuals from at least 76 institutions responded to the survey. A majority (60%) had a DATA 2000 X-waiver, 21% were board-certified in addiction medicine (AM), and an additional 22% were definitely or possibly planning to pursue board certification in AM. Sixteen percent of respondents reported having a formal leadership role to address opioid pain management and stewardship, and 17% had a formal leadership role that specifically addresses clinical treatment for OUD within their institution. Fifty-seven respondents prescribed buprenorphine in emergency medicine practice, 41 as inpatient consultants, and 23 in an outpatient clinic., Conclusions: Medical toxicologists can serve as leaders to promote safe opioid prescribing practices through both institutional and governmental opioid task forces and opioid stewardship programs. They also provide important addiction-related clinical care to patients with OUD.

Introduction: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS)., Methods: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test., Results: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4-1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4-1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4-1.6)., Conclusion: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed.

Background: Individuals who have tested positive for cocaine have claimed that lidocaine, or its primary metabolite, norlidocaine (monoethylglycinexylidide (MEGX)), have caused false positive results for the cocaine metabolite benzoylecgonine (BE) on urinary immunoassay testing., Objective: The goal of the study was to determine if lidocaine exposure from routine medical procedures can result in false positives on a commercially available cocaine immunoassay urine drug screen (UDS)., Methods: We performed a cross-sectional observational study of patients receiving lidocaine as part of their regular care. Standard immunoassay drug screens and confirmatory liquid chromatography-mass spectrometry (LC-MS) were performed on all urine samples to assess for MEGX and BE., Results: In total, 168 subjects were enrolled; 121 samples positive for lidocaine were ultimately included for analysis. One hundred fourteen of the 121 were also positive for MEGX. None of the 121 were positive for cocaine/BE on the UDS (95% CI), 0-3.7% for the full sample and 0-3.9% for the 114 who tested positive for MEGX., Conclusion: The present study found no evidence that lidocaine or norlidocaine are capable of producing false positive results on standard cocaine urine immunoassays.

Background: Despite multiple treatment options, antihypertensive overdose remains a cause of significant morbidity and mortality. Intravenous angiotensin II (AG II) is approved for use in vasodilatory shock. We describe 2 cases of refractory shock from antihypertensive overdose that were successfully treated using AG II., Case Reports: A 24-year-old female presented after an overdose of multiple antihypertensive medications, including an angiotensin converting enzyme inhibitor (ACEI). She developed hypotension that was refractory to norepinephrine, epinephrine, and vasopressin, with a mean arterial pressure (MAP) of 57 mm Hg 9 h after emergency department arrival. Fifteen minutes after starting AG II at 10 ng/kg/min, her heart rate and MAP rose by 7 beats/min and 12 mm Hg, respectively. Her hemodynamic parameters continued to improve thereafter. She developed acute kidney injury, which resolved prior to discharge. The second patient, a 65-year-old male, presented after an overdose of multiple antihypertensive medications, including an ACEI. Despite norepinephrine, epinephrine, and hyperinsulinemia-euglycemia, he remained bradycardic and hypotensive, with a heart rate of 47 beats/min and MAP of 59 mm Hg. Thirty minutes after starting AG II at 10 ng/kg/min, his heart rate was 61 beats/min and MAP was 66 mm Hg. He recovered without apparent sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Antihypertensive overdose can lead to shock refractory to catecholamine and vasopressin therapy. Our experience suggests that AG II is efficacious in antihypertensive overdose and may be particularly efficacious in instances of ACEI overdose. However, further study is required to confirm the appropriate indication(s)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance : Tramadol prescriptions have increased as fewer schedule II and III drugs are prescribed. There has been a concomitant increase in overdoses and adverse events recorded in the National Poison Data System. Seizure activity after tramadol overdose or therapeutic use is a well-documented adverse event. The primary objective is to evaluate the characteristics associated with seizures following single agent tramadol ingestion. Secondarily we aim to compare the rate of seizures in individuals treated, and not treated, with naloxone. Methods : We searched the Toxicology Investigators Consortium data registry for all cases of single agent tramadol ingestions from 01/01/2014 through 12/31/2017. Descriptive statistics were used to evaluate characteristics associated with increased risk of seizures. Binary logistic regressions were used to evaluate the associations between seizures and age, race, acuity, intent, toxidromes, symptoms, and treatments. Results : There were 80 single ingestion tramadol cases entered into the registry. Seizures developed in 42 (52.5%) patients. Asian patients (OR = 7.2, 95% CI: 1.9-27.3, p  = .004) and patients abusing or misusing tramadol (OR = 3.2, 95% CI: 1.2-8.3, p  = .02) more likely to develop seizures. Patients exhibiting an opioid toxidrome were significantly less likely to develop seizures (OR = 0.12, 95% CI: 0.03-0.60). Ingestion of tramadol as a means of self-harm and age were not associated with an increased risk of seizures. There was no significant association between naloxone administration and seizures (OR = 0.30, 95% CI 0.07-1.25). Conclusions : Based on data from the ToxIC registry, tramadol induced seizures are more likely in Asian patients and those abusing or misusing the medication. There was no association found between the development of seizures and the use of naloxone.

Background: The Emergency Department (ED) frequently treats patients with drug overdoses and is an important resource for individuals with opioid use disorder who are seeking treatment. Initiating medication-assisted treatment (MAT) in the ED seems to be an effective way to link patients with opioid use disorder (OUD) to treatment programs. There is ongoing discussion on the best approach to MAT in the ED setting., Objective: Describe a new model for managing OUD in the ED., Method: Information was obtained retrospectively from the electronic medical records of patients seen in a large county tertiary care center's Clinical Decision Unit (CDU) for OUD between September 1, 2017 and February 6, 2018. Data were summarized descriptively., Results: There were 18 different patients placed in the CDU during the study period. Ninety-five percent were induced with buprenorphine-naloxone in the CDU. The median initial Clinical Opioid Withdrawal Scale score at the time of induction was 10. The median total dose of buprenorphine-naloxone that was administered was 8/2 mg. The median amount of time spent in the CDU and ED combined was 23 h. Approximately (12/19) 63% of subjects went to their initial follow-up appointment in clinic. Nine were still active in clinic at 30 days and 4 were active at 6 months., Conclusions: This retrospective chart review shows promising preliminary data for managing OUD in an ED CDU. Such strategies have the potential to increase access to care in a vulnerable patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)