Withdrawal Symptoms Research Articles

Impact of Heating Conventional Cigarettes with a Novel Device on Health-related Biomarkers and Cigarette Use Patterns among Chinese Adult Smokers Unwilling to Quit: A Pilot Randomized Controlled Trial.

We evaluated the impact of heating conventional cigarettes with a novel heated tobacco product (HTP) device on biomarkers and cigarette use patterns in Chinese adult smokers unwilling to quit smoking. In this pilot randomized controlled trial, 50 eligible participants were allocated to either Control group (smoking conventional cigarettes) or HTP device group (switching to using heated conventional cigarettes by the HTP device). Participants in the HTP device group went through a 2-day run-in period then used heated conventional cigarettes exclusively for 5 days, followed by flexible use for 14 days. Five biomarkers of exposure (BoEs) were measured at baseline and on Day 7. Thirteen biomarkers of biological effect (BoBEs) were measured at baseline and on Day 21. Safety, daily cigarette consumption, craving, withdrawal symptoms, and device acceptability, were assessed. BoE levels decreased by 26.4 % to 71.4% from baseline in the HTP device group, while BoBE levels did not significantly change in either group. In the HTP group, 56% exclusively used heated conventional cigarettes during the flexible use period, experiencing reduced cravings and withdrawal symptoms, while dual users consumed more cigarettes. Mild to moderate device-related reactions were reported in 36% of users. Satisfaction, taste, and harm reduction belief scores averaged 7.4, 6.6, and 8.7 (out of 10), respectively. Switching to heated cigarettes with the HTP device may reduce short-term exposure to smoke toxicants. However, it can lead to increased tobacco use among dual users. Further investigation is needed to confirm these preliminary findings. This study is the first to evaluate the impact of heating conventional cigarettes with a novel heated tobacco product (HTP) device on health-related biomarkers and cigarette use patterns among Chinese adult smokers. This novel HTP device can directly heat conventional cigarettes without the necessity for specifically designed tobacco products, avoiding potential additive risks of traditional HTPs. If the results of this study could be further verified by randomized controlled clinical trials with larger sample sizes, this novel HTP device could serve as a short-term harm reduction alternative for smokers unwilling to quit.

A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence

BackgroundPrevious studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. MethodOur sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. ResultsThere were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. ConclusionCannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

Use and perceptions of Cannabidiol among individuals in treatment for opioid use disorder

BackgroundCannabidiol (CBD) is a widely available cannabis product with many claims as to potential health benefits including alleviating symptoms related to opioid use disorder (OUD). However, little is known as to how individuals with OUD perceive CBD, to what extent they may already be using CBD, and for what purposes.MethodsA survey was conducted among individuals receiving treatment for OUD at the Addiction Institute of Mount Sinai in New York City from July 2021 to August 2023. The survey consisted of demographic questions, questions about opioid use, CBD use, and perceptions regarding CBD. Statistical analysis using ordinal logistic regression was employed to compare perceptions between CBD users and non-users while adjusting for age and race.ResultsAmong 587 respondents, 550 completed the survey. Among all survey completers, 129 (23%) reported a history of using CBD for a variety of reasons including: anxiety (81, 62.8%), pain (65, 50.4%), sleep (63, 48.8%), depression (62, 48.1%), recreational purposes (32, 24.8%), or for other reasons (8, 6.2%). Of note, 22 (17.1%) respondents reported using CBD to control their addiction and 54 (41.9%) reported using CBD to ease opioid withdrawal symptoms. CBD users demonstrated more positive perceptions regarding its legality (β = 0.673, OR = 1.960, 95% CI [1.211, 3.176], p = .006), social acceptance (β = 0.718, OR = 2.051, 95% CI [1.257, 3.341], p = .004), and therapeutic potential compared to non-users. CBD users also had a more positive view of its potential future role in managing addiction (β = 0.613, OR = 1.846, 95% CI [1.181, 2.887], p = .007).ConclusionsThis study highlights a significant association between CBD usage and progressive views regarding CBD among individuals with OUD, suggesting a growing interest in CBD as a potential adjunctive therapy for individuals in substance use treatment. Some patients are already using CBD for anxiety, pain, sleep, depression, or as a harm reduction intervention to control their addiction or for opioid withdrawal symptoms. These findings underscore the importance of integrating patient perspectives into future research and treatment strategies involving CBD in the context of OUD.

Assessing predictors of adequate individual buprenorphine maintenance dosage for the treatment of opioid use disorder: Listening to the patient

ObjectiveDose optimization plays a key role in determining clinical outcomes in patients on opioid agonist treatment (OAT). The objective of this study was to identify the variables independently associated with buprenorphine/naloxone (B/N) dose adequacy in patients with opiate use disorder (OUD). MethodCross-sectional study of a convenience sample of patients with OUD treated with B/N (n = 315) in four regions in Spain. The Opiate Dosage Adequacy Scale (ODAS) was used to determine B/N dose adequacy. The ODAS evaluate the six components of the “dose adequacy” construct, as follows: continued use of heroin; narcotic blockade or crossed tolerance; objective opioid withdrawal symptoms (OWS); subjective OWS; craving for heroin; and overmedication. A binomial logistic regression analysis was performed to identify the variables associated with the condition “ODAS Adequate B/N dose”. Participants completed a battery of instruments to assess sociodemographic, substance use, clinical, and treatment variables. ResultsThe B/N dose was considered adequate in 231 of the 315 participants (73.3 %). Two variables, satisfaction with B/N as a medication (OR=5.764, 95 % CI=2.211-15.030) and patient-perceived participation in B/N dose decisions (OR=1.790, 95 % CI=1221-2623), were independently, significantly, and positively associated with the “ODAS Adequate B/N dose” condition. While the severity of heroin dependence was significantly associated with buprenorphine dose adequacy in the bivariate analyses, significance was lost in the full regression model. ConclusionSatisfaction with B/N as a medication and patient-perceived involvement in the dose decision are associated with clinician-assessed dose adequacy. In the context of good clinical practice, it is important to take into account both of these variables to individualize the prescribed dose through a shared decision-making process.

Neonatal abstinence syndrome and infant mortality and morbidity: a population-based study

BackgroundInfant health among newborns with neonatal abstinence syndrome (NAS) has been understudied. We examined infant mortality and hospitalizations among infants diagnosed with NAS after birth.MethodsAll live births in British Columbia (BC), Canada, for fiscal years from 2004–2005 to 2019–2020, were included (N = 696,900). NAS was identified based on International Classification of Diseases, version 10, Canadian modification (ICD-10-CA) codes; the outcomes included infant death and hospitalizations during the first year of life, ascertained from BC linked administrative data. Generalized estimating equation models were used to adjust for maternal factors.ResultsThere were 2,439 infants with NAS (3.50 per 1,000 live births). Unadjusted for other factors, infant mortality was 2.5-fold higher in infants with vs. without NAS (7.79 vs. 3.08 per 1,000 live births, respectively) due to increased post-discharge mortality NAS (5.76 vs. 1.34 per 1,000 surviving infants, respectively). These differences diminished after adjustment: adjusted odds ratio (AOR) for infant death was 0.85 [95% confidence interval (CI): 0.52–1.39]; AOR for post-discharge death was 1.75 (95% CI 1.00–3.06). Overall, 22.3% infants with NAS had at least one hospitalization after post-neonatal discharge, this proportion was 10.7% in those without NAS. During the study period, discharge to foster care declined from 49.5% to 20.3% in infants with NAS.ConclusionUnadjusted for other factors, infants with NAS had increased post-discharge infant mortality and hospitalizations during the first year of life. This association diminished after adjustment for adverse maternal and socio-medical conditions. Infants with NAS had a disproportionately higher rate of placement in foster care after birth, although this proportion declined dramatically between 2004/2005 and 2019/2020. These results highlight the importance of implementing integrated care services to support infants born with NAS and their mothers during the first year of life and beyond, even though NAS itself is not independently associated with increased infant mortality.

Management of alcohol withdrawal syndrome (AWS)

Alcohol withdrawal syndrome (AWS) is a complex set of symptoms that occur in alcohol-dependent individuals after sudden withdrawal or a significant reduction in alcohol consumption. AWS symptoms occur in about 50% of alcohol abusers. These symptoms may include restlessness, tremor, nausea, nervousness, tachycardia, elevated blood pressure, hyperhidrosis, insomnia, hyperactivity, and hallucinations. In some cases, seizures may occur and delirium tremens may develop, which is life-threatening and an absolute indication for hospitalization of the patient. Effective treatment of AWS is the key to prevent complications and to reduce the risk of death. Treatment of alcohol withdrawal syndrome requires a complex approach that combines properly performed diagnosis, careful monitoring of the patient's condition, pharmacotherapy, equalization of electrolyte disorders, adequate hydration of the patient, supplementation of thiamine deficiencies and, in the case of symptoms of alcoholic delirium, intensive medical care. Pharmacological treatment plays a key role, with the first line of treatment being benzodiazepines, which reduce the risk of epileptic seizures and delirium tremens, and reduce mortality in the course of AWS. Individualized therapy adjustment and patient monitoring are crucial to ensure effective and safe treatment.

Liraglutide in the management of obesity: real world data (Portugal).

Overweight and obesity are major public health issues with increasing incidence and prevalence, affecting more than 50% of the population in developed countries. Due to its complex pathophysiology and multifactorial etiology, disease understanding, diagnostic approach and management remain suboptimal. Together with a structured nutritional intervention and physical activity plan, pharmacological treatment has the potential to magnify weight loss and health related benefits. Liraglutide is one of the most effective and frequently prescribed weight loss medication. Its efficacy and safety have been demonstrated in randomized clinical trials, however, real world data in Portugal is scarce. The authors report on the experience of a University Hospital Endocrine Clinic in the management of patients with overweight and obesity with liraglutide on top of lifestyle intervention. The aim of the study was to evaluate the effectiveness of liraglutide in the management of overweight and obesity. Retrospective, longitudinal observational study. Inclusion criteria were adult patients (>18 years old) with obesity (BMI>30 kg/m2) or overweight (≥27 kg/m2) with at least one obesity related co-morbidity (hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease) with at least three months of liraglutide treatment. Diabetes diagnosis and prior bariatric surgery were exclusion criteria. Demographic and clinical variables were included and weight was recorded before and after at least 3 months of liraglutide treatment. One hundred forty-eight patients (85.8% females) with a mean age of 48.7±11.9 years were treated with liraglutide. Mean baseline BMI was 33.8±5.2 kg/m2 and median follow-up was 13 months. At the last appointment, 85.8% were still taking liraglutide. Among patients still taking liraglutide, mean weight loss was 7.6 kg (7.9%), with significantly greater losses in patients treated for more than 6 months (8.6kg vs. 6.2 kg, P=0.016). Patients with obesity lost significantly more weight than overweight patients (8.3 kg vs. 4.5 kg, P=0.028), despite similar treatment duration. The reasons for liraglutide withdrawal were gastrointestinal intolerance (7), medication cost (2), inefficacy (10) and physician instructions (1). The present study documents the long-term efficacy of liraglutide in the treatment of patients with overweight and obesity, with a low rate of drug withdrawal. Mean weight loss was significant and more evident from the 6th month of treatment on. Liraglutide, along with lifestyle intervention, is a good option for weight management in the majority of patients with obesity.

Buprenorphine vs. morphine: impact on neonatal opioid withdrawal syndrome (NOWS) outcomes in a single center retrospective study.

To compare clinical outcomes for infants with neonatal opioid withdrawal syndrome (NOWS) treated with buprenorphine or morphine. Retrospective study of infants born ≥35 weeks' gestation and admitted to the NICU for NOWS treatment between 2011 and 2022. Length of treatment, length of stay in the hospital, and the need for secondary medications were compared between buprenorphine and morphine treated neonates. Multiple regression analysis was performed, adjusting for baseline differences and confounders. 417 neonates were treated with morphine and 232 with buprenorphine. The buprenorphine group had shorter treatment days [-10.8 days; 95% CI: -8.08 to -13.53] and shorter hospital stay [-11.8 days; 95% CI: -8.83 to -14.78]. The buprenorphine group was no more likely to receive phenobarbital or clonidine (26% vs. 29%). In this large single-center study, buprenorphine was associated with shorter lengths of treatment and hospital stay in the treatment of NOWS compared to morphine.

T8 - Association of Baseline Fentanyl Use and Opioid Withdrawal Symptoms During Inpatient Buprenorphine Initiation in a Large Multisite Detoxification Trial

T8 - Association of Baseline Fentanyl Use and Opioid Withdrawal Symptoms During Inpatient Buprenorphine Initiation in a Large Multisite Detoxification Trial

M80 - Opioid Withdrawal Symptoms and Reasons for Discontinuation of Low-Dose Buprenorphine Induction for Treatment of Opioid Use Disorder in Hospitalized Patients

M80 - Opioid Withdrawal Symptoms and Reasons for Discontinuation of Low-Dose Buprenorphine Induction for Treatment of Opioid Use Disorder in Hospitalized Patients

Clinical characteristics and prognosis of pancreatitis associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have shown remarkable efficacy against various cancers in clinical practice. However, ICIs can cause immune checkpoint inhibitor-associated pancreatic injury, often leading to drug withdrawal, and then patients must go to specialized treatment. The patients, their primary tumors are sensitive to ICIs therapy, may experience treatment delays due to such adverse reactions. Therefore, there is a need for systematic clinical researches on immune-related pancreatic toxicity to provide a clinical basis for its prevention and treatment. This study involved the collection of data from patients treated with ICIs and addressed pancreatic injury with preemptive treatment before continuing ICIs therapy. Then, we also statistically analyzed the incidence of pancreatic injury in patients with different courses and combined treatment, and the success rate of rechallenge treatment. The study included 62 patients, with 33.9% (21/62) experiencing varying degrees of pancreatic injury. Patients with pancreatic injury, 10 cases evolved into pancreatitis, representing 47.6% (10/21) in the pancreatic injury subgroup and 16.1% (10/62) of the total patient cohort. Preemptive treatment was administered to 47.6% (10/21) of patients with pancreatitis, the effective rate was 100%. Among these patients, 70% (7/10) underwent successful rechallenge with ICIs. The occurrence of pancreatic injury was positively correlated with the treatment duration (P < 0.05) but showed no significant correlation with combination therapies (P > 0.05). The likelihood of pancreatic injury increased with longer treatment durations with ICIs; no significant association was found between the incidence of ICIs-related pancreatic damage and combination therapies. Preemptive treatment for immune-related pancreatitis is feasible, allowing some patients to successfully undergo rechallenge with ICIs therapy.

Machine learning and deep learning approaches for enhanced prediction of hERG blockade: a comprehensive QSAR modeling study

ABSTRACT Background Cardiotoxicity is a major cause of drug withdrawal. The hERG channel, regulating ion flow, is pivotal for heart and nervous system function. Its blockade is a concern in drug development. Predicting hERG blockade is essential for identifying cardiac safety issues. Various QSAR models exist, but their performance varies. Ongoing improvements show promise, necessitating continued efforts to enhance accuracy using emerging deep learning algorithms in predicting potential hERG blockade. Study design and method Using a large training dataset, six individual QSAR models were developed. Additionally, three ensemble models were constructed. All models were evaluated using 10-fold cross-validations and two external datasets. Results The 10-fold cross-validations resulted in Mathews correlation coefficient (MCC) values from 0.682 to 0.730, surpassing the best-reported model on the same dataset (0.689). External validations yielded MCC values from 0.520 to 0.715 for the first dataset, exceeding those of previously reported models (0–0.599). For the second dataset, MCC values fell between 0.025 and 0.215, aligning with those of reported models (0.112–0.220). Conclusions The developed models can assist the pharmaceutical industry and regulatory agencies in predicting hERG blockage activity, thereby enhancing safety assessments and reducing the risk of adverse cardiac events associated with new drug candidates.

Patterns of Pregabalin Users from Substance Abuse Treatment Facilities: Results from the French OPPIDUM Program from 2008 to 2022.

In recent years, pregabalin has received growing attention due to its abuse liability. The aim of this study was to further characterize patterns of pregabalin users from substance abuse treatment facilities and detect changes in users profile over the study period. The data source was the Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse (OPPIDUM) program, an annual, repeated, cross-sectional, nationwide, multicenter survey that collects consumption data from patients with substance use disorders. First, we described the characteristics of pregabalin users and their consumption patterns. We compared these data between 2008 and 2018 (P1) and 2019 and 2022 (P2). Second, we conducted a multiple correspondence analysis to identify profiles of users. From 2008 to 2022, 291 pregabalin users (0.37% of all users) from 116 substance abuse treatment facilities were identified. The number of pregabalin users was lower than 15 per year in P1 (n = 89) and between 40 and 60 per year in P2 (n = 202). The number of users who reported pregabalin as the first substance leading to dependence increased significantly in P2 compared with P1 (p < 0.005). When comparing P2 with P1, there was a significant increase in precarity (p < 0.001), users in prison (p = 0.002), withdrawal symptoms (p < 0.001), dependence (p < 0.001), use of higher dose of pregabalin (p = 0.029), and acquisition by deal/street market (p < 0.001). The multiple correspondence analysis allowed for the identification of distinct profiles of pregabalin users: (i) a cluster with mainly users from P1, who presented a simple use of pregabalin, and were older (> 45 years), were involved in opioid agonist treatment (OAT), and obtained pregabalin legally; and (ii) a cluster with mainly users from P2, who presented pregabalin dependence, and were younger (< 26 years), reported pregabalin as the first substance leading to dependence, used doses higher than the market authorization, were in severe precarity, and were in prison. These data showed that the profile of pregabalin users has changed in the last years. Pregabalin use disorders also affect users without history of addiction.

BACLOFEN PREVENTS MORPHINE REWARDING EFFECTS AND ASSOCIATED BIOCHEMICAL ALTERATIONS IN MALE AND FEMALE MICE

Previous studies from our laboratory have shown sex differences in the behavioral, molecular, and neurochemical manifestations of morphine withdrawal and they were related to an increased sensitivity to morphine effects in males. In addition, we observed an interaction between the GABAergic and opioid systems that could also be sex-dependent. Baclofen, a GABAB receptor agonist, prevented the somatic expression and the molecular and neurochemical changes induced by morphine withdrawal syndrome in mice. On the contrary, little is known about baclofen effects in the rewarding properties of morphine in male and female mice. The present study aimed to explore the effect of baclofen (1, 2 and 3 mg/kg, i.p.) pretreatment in the rewarding effects induced by morphine (7 mg/kg, s.c.) and its effect on c-Fos and brain-derived neurotrophic factor (BDNF) expression induced by the rewarding properties of morphine in prepubertal male and female mice. Baclofen (2 mg/kg) pretreatment prevented the rewarding effects of morphine only in male mice, while baclofen (3 mg/kg) reduced these effects in both sexes. Moreover, the rewarding effects of morphine were associated with a decrease of BDNF and c-Fos expression cingulate cortex, nucleus accumbens shell, cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) areas of the hippocampus only in male mice. In addition, baclofen pretreatment prevented these changes in BDNF, but not in c-Fos expression. In conclusion, our results show that GABAB receptors have a regulatory role in the rewarding effects of morphine that could be of interest for a potential future therapeutic application in opioid use disorders.

Evaluating drug withdrawal syndrome risks through food and drug administration adverse event reporting system: a comprehensive disproportionality analysis

ObjectiveThe study aims to identify the drugs associated with drug withdrawal syndrome in the Food and Drug Administration Adverse Event Reporting System (FAERS) and estimate their risks of causing withdrawal syndrome.MethodsAll the data were collected from FAERS from the first quarter of 2004 to the third quarter of 2023. Disproportionality analyses of odds ratio (ROR) and proportional reported ratio were conducted to identify potential adverse effects signal of drug withdrawal syndrome.ResultsA total of 94,370 reports related to withdrawal syndrome from the data. The top 50 drugs with most frequency reported were analyzed, and 29 exhibited a positive signal based on the number of reports. The top three categories of drugs with positive signals included opioids, antidepressant drugs and antianxiety drugs. Other classifications included opioid antagonist, muscle relaxant, antiepileptic drugs, analgesics, hypnotic sedative drugs and antipsychotic drugs.ConclusionOur analysis of FAERS data yielded a comprehensive list of drugs associated with withdrawal syndrome. This information is vital for healthcare professionals, including doctors and pharmacists, as it aids in better recognition and management of withdrawal symptoms in patients undergoing treatment with these medications.

Development of clinical prediction model to guide the use of CT head scans for non-traumatic Thai patient with seizure: A cross-sectional study.

The aim of this study was to develop clinical predictor tools for guiding the use of computed tomography (CT) head scans in non-traumatic Thai patients presented with seizure. A prediction model using a retrospective cross-sectional design was conducted. We recruited adult patients (aged ≥ 18 years) who had been diagnosed with seizures by their physicians and had undergone CT head scans for further investigation. Positive CT head defined as the presence of any new lesion that related to the patient's presented seizure officially reported by radiologist. A total of 9 candidate predictors were preselected. The prediction model was developed using a full multivariable logistic regression with backward stepwise elimination. We evaluated the model's predictive performance in terms of its discriminative ability and calibration via AuROC and calibration plot. The application was then constructed based on final model. A total of 362 patients were included into the analysis which comprising of 71 patients with positive CT head findings and 291 patients with normal results. Six final predictors were identified including: Glasgow coma scale, the presence of focal neurological deficit, history of malignancy, history of CVA, Epilepsy, and the presence of alcohol withdrawal symptom. In terms of discriminative ability, the final model demonstrated excellent performance (AuROC of 0.82 (95% CI: 0.76-0.87)). The calibration plot illustrated a good agreement between observed and predicted risks. This prediction model offers a reliable tool for effectively reduce unnecessary use and instill confidence in supporting physicians in determining the need for CT head scans in non-traumatic patients with seizures.

Improved Detection of Drug-Induced Liver Injury by Integrating Predicted In Vivo and In Vitro Data.

Drug-induced liver injury (DILI) has been a significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. Over the last decade, the existing suite of in vitro proxy-DILI assays has generally improved at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing the in silico prediction of DILI because it allows for evaluating large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects. In this study, we aim to study ML models for DILI prediction that first predict nine proxy-DILI labels and then use them as features in addition to chemical structural features to predict DILI. The features include in vitro (e.g., mitochondrial toxicity, bile salt export pump inhibition) data, in vivo (e.g., preclinical rat hepatotoxicity studies) data, pharmacokinetic parameters of maximum concentration, structural fingerprints, and physicochemical parameters. We trained DILI-prediction models on 888 compounds from the DILI data set (composed of DILIst and DILIrank) and tested them on a held-out external test set of 223 compounds from the DILI data set. The best model, DILIPredictor, attained an AUC-ROC of 0.79. This model enabled the detection of the top 25 toxic compounds (2.68 LR+, positive likelihood ratio) compared to models using only structural features (1.65 LR+ score). Using feature interpretation from DILIPredictor, we identified the chemical substructures causing DILI and differentiated cases of DILI caused by compounds in animals but not in humans. For example, DILIPredictor correctly recognized 2-butoxyethanol as nontoxic in humans despite its hepatotoxicity in mice models. Overall, the DILIPredictor model improves the detection of compounds causing DILI with an improved differentiation between animal and human sensitivity and the potential for mechanism evaluation. DILIPredictor required only chemical structures as input for prediction and is publicly available at https://broad.io/DILIPredictor for use via web interface and with all code available for download.

Polymyxin B neurotoxicity as manifestation of a serious life-threatening adverse reaction: clinical case

The aim of this work is to describe a clinical case of a serious life-threatening adverse reaction in the form of neurotoxicity (convulsions, apnea requiring mechanical ventilation) to the polymyxin B drug, and also to remind that manifestations of neurotoxicity can be extremely varied and nonspecific, and do not occur after every administration, can be delayed, require vigilance and careful monitoring both from the attending physicians and from anesthesiologistsresuscitators, neurologists, ophthalmologists, etc.A 62-year-old female patient diagnosed with stage IIIB T4G3N0M0 pleomorphic soft tissue sarcoma of the right thigh, condition after combination treatment, developed infection and necrosis of the postoperative wound (recto-abdominal flap). According to the results of a microbiological study and an antibiogram, the patient received polymyxin B as part of combination antibacterial therapy. On days 4, 5, 6, 7 of polymyxin administration, the patient experienced the following symptoms in various combinations: weakness, numbness of the face, paresthesia, paresis of the limbs, partial convulsions, respiratory depression, and apnea.After establishing a connection between neurologicalsymptoms and intravenous administration of polymyxin B (the total score on the Naranjo scale was 6 points, the degree of reliability of the “adverse reaction–drug” relationship was probable) and drug withdrawal, manifestations of neurotoxicity completely disappeared and did not reoccur. The patient was discharged in satisfactory condition.In a patient with symptoms of damage to the nervous system, it is necessary to conduct multiple differential diagnostic search to exclude stroke, epilepsy, encephalitis, hereditary and acquired neurodegenerative diseases, as well as side effects of medications. At the slightest suspicion of the likelihood of an adverse reaction to polymyxin B/colistimethate sodium, the Naranjo algorithm must be used to establish a cause-and-effect relationship between the adverse reaction and the drug.

Initiation of Buprenorphine Treatment of Opioid Use Disorder in Pediatric Emergency Departments.

Pediatric emergency departments (EDs) in the United States are facing a rise in the number of children and adolescents who present with opioid use disorder (OUD), often driven by illicitly manufactured fentanyl. Medication treatment of pediatric OUD in the ED setting is often limited to symptomatic treatment of opioid withdrawal. Pediatric patients are rarely offered medications for OUD, especially in the ED setting. Buprenorphine is a partial opioid agonist that is Food and Drug Administration-approved for the treatment of OUD in patients aged 16 years and older. Adult studies have demonstrated that ED initiation of medication for OUD such as buprenorphine is feasible, safely treats withdrawal symptoms, and can improve patient compliance with outpatient follow-up. However, initiation of buprenorphine in the ED has not been well-studied in the pediatric population. We present 2 cases of adolescent patients, a 16-year-old male and 17-year-old female, who presented to the ED with opioid withdrawal. They were both diagnosed with severe OUD because of their use of counterfeit pills containing fentanyl. Both patients were successfully started on buprenorphine/naloxone in the pediatric ED before transitioning to an outpatient addiction clinic for continued treatment. The case series demonstrates the feasibility of ED-based buprenorphine initiation for adolescents, an important and timely intervention for adolescents with OUD.

Diagnosis and Treatment of Presumed Naltrexone-XR-precipitated Opioid Withdrawal in a Patient Chronically Treated With Buprenorphine-XR: A Case Report.

Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment.