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The American Journal of Emergency... May 2024Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with...
BACKGROUND
Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with olanzapine. Samidorphan is an analog of naltrexone, initially intended to treat substance use disorders by antagonizing mu, delta, and kappa opioid receptors.
CASE REPORT
We present the case of a 36-year-old who took their first dose of olanzapine/samidorphan shortly before calling for emergency services. The patient took diphenhydramine and an epinephrine autoinjector for what they thought was an allergic reaction but continued to have symptoms. EMS reported involuntary muscle movements thought to be due to dystonia from olanzapine. In the ED, they experienced generalized muscle spasms lasting for several seconds and diaphoresis. Initially, the staff treated for a presumed dystonic reaction to olanzapine and administered diphenhydramine 25 mg IV, diazepam 2 mg IV, midazolam 5 mg IV, and benztropine 1 mg IV without improvement. It was later determined that the patient took 16 mg of buprenorphine SL daily. With this information, precipitated opioid withdrawal was felt to be the likely cause of symptoms. The patient received 16 mg of buprenorphine for an initial Clinical Opiate Withdrawal Scale (COWS) score of 11 with repeat COWS of 6. Why should an emergency physician be aware of this? Initiating olanzapine/samidorphan in the setting of chronic opioid therapy may result in precipitated opioid withdrawal. Additional SL buprenorphine may be a reasonable treatment modality.
Topics: Female; Animals; Cattle; Humans; Adult; Olanzapine; Narcotic Antagonists; Analgesics, Opioid; Naltrexone; Buprenorphine; Substance Withdrawal Syndrome; Diphenhydramine; Opioid-Related Disorders
PubMed: 38556414
DOI: 10.1016/j.ajem.2024.03.027 -
International Review of Neurobiology 2024Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in... (Review)
Review
Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.
Topics: Humans; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Sodium Oxybate; Baclofen; Drug Repositioning; Substance Withdrawal Syndrome; Alcohol Drinking
PubMed: 38555115
DOI: 10.1016/bs.irn.2024.02.002 -
Brain, Behavior, and Immunity Jul 2024GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic...
GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.
Topics: Pyroptosis; Parkinson Disease; Animals; Dopaminergic Neurons; Microglia; Mice; Male; Humans; Phosphate-Binding Proteins; Disulfiram; Mice, Inbred C57BL; Disease Models, Animal; Cell Death; Mice, Knockout; Gasdermins
PubMed: 38552923
DOI: 10.1016/j.bbi.2024.03.038 -
Cells Mar 2024Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through...
Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through its copper chelating derivatives and induction of oxidative stress in mitochondria. Since chronic/persistent borreliosis is characterized by increased amounts of pro-inflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration, and surface marker expression of in vivo activated and in vitro cultured human monocyte-derived phagocytes (macrophages and dendritic cells) with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24 h, imaging every 3.5 min. To simultaneously monitor phagocyte function, results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads. DSF decreased the phagocytic capacities exhibited by in vitro enriched and long-lived phagocytes. Although no chemotactic gradient was applied to the test system, vigorous spontaneous migration was observed. We therefore set up an algorithm to monitor and quantify both phagocytosis and migration simultaneously. DSF not only reduced phagocytosis in a majority of these long-lived phagocytes but also impaired their migration. Despite these selective effects by DSF, we found that DSF reduced the expression densities of surface antigens CD45 and CD14 in all of our long-lived phagocytes. In cells with a high metabolic activity and high mitochondrial contents, DSF led to cell death corresponding to mitochondrial oxidative stress, whereas metabolically inactive phagocytes survived our DSF treatment protocol. In conclusion, DSF affects the viability of metabolically active phagocytes by inducing mitochondrial stress and secondly attenuates phagocytosis and migration in some long-lived phagocytes.
Topics: Humans; Disulfiram; Opsonin Proteins; Phagocytosis; Phagocytes; Macrophages
PubMed: 38534379
DOI: 10.3390/cells13060535 -
Journal of Opioid Management 2024Tianeptine, an antidepressant and full µ-opioid receptor agonist, has increased in popularity and has been used as an over-the-counter supplement over the past decade....
Tianeptine, an antidepressant and full µ-opioid receptor agonist, has increased in popularity and has been used as an over-the-counter supplement over the past decade. Due to its well-documented euphoric effects, there exists elevated risk for potential abuse. Buprenorphine-naloxone has been successfully utilized to treat opioid use disorder (OUD) in patients concurrently using tianeptine, limiting withdrawal symptoms and abstinence. However, there is limited evidence on the management of tianeptine use disorder, specifically methadone or naltrexone. The current opioid epidemic, the emerging use of tianeptine, and the lack of physician awareness have emphasized the need for further research on the role of tianeptine in medication-assisted treatment for OUD. This case report aims to demonstrate how medication-assisted therapy can be successfully utilized in a patient with opioid and severe other (tianeptine) drug use disorder.
Topics: Humans; Methadone; Analgesics, Opioid; Buprenorphine; Opiate Alkaloids; Opiate Substitution Treatment; Opioid-Related Disorders; Naltrexone; Thiazepines
PubMed: 38533719
DOI: 10.5055/jom.0851 -
Journal of Opioid Management 2024Naltrexone (NTX) is an orally effective opiate antagonist used in maintenance treatment for opiate dependence. Its utility is limited by the patient's noncompliance. The...
Naltrexone (NTX) is an orally effective opiate antagonist used in maintenance treatment for opiate dependence. Its utility is limited by the patient's noncompliance. The study aimed to develop an efficient method for the detection of NTX in urine by LC-QTOF-mass spectrometry (MS) and its application to NTX compliance in opioid-dependent subjects. Sample preparation included a dilution step and direct injection to LC-QTOF-MS. Chromatographic separation was achieved with a C-18 column using a mixture of mobile phase 0.1 percent formic acid in water and 0.1 percent formic acid in 95 percent methanol. The calibration curve was linear in the range 1-100 ng/mL with a correlation coefficient higher than 0.996. Precision and accuracy were acceptable, and the recovery efficiency range was 80-85 percent. The current LC-QTOF-MS method is simple, precise, sensitive, and can be used for monitoring NTX compliance among opioid-dependent subjects in a clinical setting.
Topics: Humans; Analgesics, Opioid; Tandem Mass Spectrometry; Formates; Naltrexone; Reproducibility of Results
PubMed: 38533710
DOI: 10.5055/jom.0841 -
Diabetes, Obesity & Metabolism Jun 2024Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes.
METHODS
Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a Tc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T) and percentage gastric retention at 1, 2 and 4 h.
RESULTS
Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal.
CONCLUSION
Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.
Topics: Humans; Gastric Emptying; Male; Female; Schizophrenia; Adult; Middle Aged; Metabolic Syndrome; Prediabetic State; Antipsychotic Agents; Receptors, G-Protein-Coupled; Cross-Over Studies; Tetrahydronaphthalenes; Naltrexone
PubMed: 38533552
DOI: 10.1111/dom.15569 -
Journal of Substance Use and Addiction... Jul 2024The opioid epidemic in the United States has not spared youth or young adults, as evidenced by a six-fold increase in opioid use disorder (OUD) diagnoses in the last two...
BACKGROUND
The opioid epidemic in the United States has not spared youth or young adults, as evidenced by a six-fold increase in opioid use disorder (OUD) diagnoses in the last two decades. Given this dramatic rise, a call for greater uptake and accessibility of medications for opioid use disorder (MOUDs) among youth and young adults has ensued, resulting in an increasing number of MOUD treatment pathways for this vulnerable population.
METHODS
This secondary data analysis seeks to characterize patient and provider preferences for MOUD treatment pathways, and test for associations between baseline MOUD treatment preferences and opioid use and treatment adherence outcomes. Participants included 288 youth and young adults (age 15-21 years), recruited from a residential treatment program in Maryland. The study assessed patient preferences at baseline (n = 253) and provider preferences at patient treatment discharge (n = 224). Mixed-effects negative binomial regression models were conducted for opioid use outcomes, and logistic regressions were conducted for treatment adherence outcomes.
RESULTS
Results indicate that congruence of treatment with patients' (Incidence Rate Ratio [IRR] = 0.65) and providers' (IRR = 0.66) preferences was significantly associated with reduced self-reported days of opioid use in the past 90 days, but only for patients receiving extended-release naltrexone (XR-NTX). Results also indicated that patients were less likely to switch medication treatment pathways (e.g., from XR-NTX to buprenorphine, or vice versa) during follow-up if they received their preferred treatment at baseline, a finding which held true for both XR-NTX (Odds Ratio [OR] = 0.32) and buprenorphine (OR = 0.22).
CONCLUSIONS
Receipt of MOUD congruent with patient and provider preferences was associated with reduced opioid use and greater treatment adherence in this sample of youth and young adults with OUD.
Topics: Humans; Adolescent; Opioid-Related Disorders; Male; Female; Young Adult; Patient Preference; Opiate Substitution Treatment; Treatment Outcome; Medication Adherence; Adult; Maryland; Naltrexone; Residential Treatment; Buprenorphine
PubMed: 38531508
DOI: 10.1016/j.josat.2024.209334 -
Drug Design, Development and Therapy 2024Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the...
PURPOSE
Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting.
PATIENTS AND METHODS
The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit.
RESULTS
A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area.
CONCLUSION
All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.
Topics: Adult; Humans; Orlistat; Topiramate; Liraglutide; Naltrexone; Bupropion; Fructose; Anti-Obesity Agents; Obesity; Body Weight; Phentermine; Weight Loss
PubMed: 38524878
DOI: 10.2147/DDDT.S445415 -
Addiction (Abingdon, England) Jul 2024Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative...
Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine-naloxone and extended-release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD.
Topics: Humans; Opioid-Related Disorders; Comparative Effectiveness Research; Narcotic Antagonists; Buprenorphine, Naloxone Drug Combination; Naltrexone; Opiate Substitution Treatment; Buprenorphine; Observational Studies as Topic; Delayed-Action Preparations; Research Design; Naloxone
PubMed: 38519819
DOI: 10.1111/add.16473