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The Journal of Biological Chemistry Jun 2024Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad....
Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression. To explore antibody applications beyond traditional heavy-light chain mAbs, we identified and biophysically characterized a novel single-domain antibody specific for fentanyl from a camelid variable-heavy-heavy (VHH) domain phage display library. Structural data suggested that VHH binding to fentanyl was facilitated by a unique domain-swapped dimerization mechanism, which accompanied a rearrangement of complementarity-determining region (CDR) loops leading to the formation of a fentanyl-binding pocket. Structure-guided mutagenesis further identified an amino acid substitution that improved the affinity and relaxed the requirement for dimerization of the VHH in fentanyl binding. Our studies demonstrate VHH engagement of an opioid and inform on how to further engineer a VHH for enhanced stability and efficacy, laying the groundwork for exploring the in vivo applications of VHH-based biologics against OUD and overdose.
PubMed: 38945452
DOI: 10.1016/j.jbc.2024.107502 -
British Journal of Anaesthesia Jun 2024
PubMed: 38944552
DOI: 10.1016/j.bja.2024.05.014 -
Journal of Stroke and Cerebrovascular... Jun 2024Anomalous vascular variants pose unique challenges in clinical management, especially in the context of neuroendovascular intervention. We present a case report...
Anomalous vascular variants pose unique challenges in clinical management, especially in the context of neuroendovascular intervention. We present a case report detailing an extremely rare anatomic variant involving the left anterior choroidal artery, which arises proximal to the fetal posterior communicating artery. Our patient presented with confusion and speech abnormalities following a benzodiazepine overdose. Subsequent computed tomography of the head revealed an aneurysm originating from the left supraclinoid carotid artery. This aneurysm was located 2 mm more proximal to the origin of the left posterior communicating artery and was initially misidentified as originating from the left posterior communicating artery due to its proximity. Further diagnostic cerebral angiography revealed an extremely rare anatomical variant where the left anterior choroidal artery anomalously arose proximal to a fetal posterior communicating artery, with the aneurysm being correctly identified as arising from the left anterior choroidal artery. The patient underwent successful detoxification and has since shown remarkable improvement, with plans for elective endovascular flow diversion treatment under dual antiplatelet therapy. Considering the critical role of the anterior choroidal artery in supplying vital cerebral structures, awareness of such variants is paramount to prevent inadvertent vascular injury and optimize patient outcomes. This case highlights the necessity of meticulous pre-procedural imaging and multidisciplinary collaboration in managing neurovascular anomalies effectively.
PubMed: 38944362
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107835 -
International Immunopharmacology Jun 2024Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol...
Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol (TAX) as one of the active components. It is a pentacyclic-triterpene compound isolated from this herb. Present work aimed to investigate the in vitro and in vivo protection effect of TAX in APAP-induced acute liver injury, and determine the potential regulatory mechamisms. The liver injury caused by APAP is attenuated by TAX, as shown by the alleviated pathological changes of mice liver and the reduced serological indexes. TAX evidently controlled the oxidative stress and liver inflammation in mice liver. In vitro studies found that TAX reversed the decrease in LO2 cell viability induced by APAP, and protected LO2 cells from APAP-induced injury. In addition, TAX reduced the secretion of inflammatory factors in RAW264.7 macrophages as induced via APAP. Besides, TAX inhibited oxidative stress in LO2 cells induced by APAP in vitro. Noteworthy, TAX enhanced protein and mRNA expressions of Nrf2 in vivo, and knockdown of Nrf2 by using adeno-associated virus (AAV)-Nrf2-KO attenuated inhibitory impact of TAX in acute liver injury induced by APAP. Also, AAV-NRF2-KO weakened the inhibitory impact of TAX against APAP-triggered liver inflammation and oxidative stress of mice liver. Moreover, TAX activated the Nrf2 signaling in APAP-induced LO2 cells, as shown by the increased nuclear Nrf2 expression together with downstream HO-1 expression in vitro. Inhibition of Nrf2 by using ML-385, anNrf2inhibitor, weakened the inhibitory effect of TAX against APAP-induced oxidative stress and cell injury in LO2 cells. Moreover, inhibition of Nrf2 attenuated anti-inflammatory effect of TAX for APAP-induced RAW264.7 cells. Collectively, TAX could protect against APAP-triggered hepatotoxicitythrough suppression of liver oxidative stress and inflammatory response in mice.
PubMed: 38943970
DOI: 10.1016/j.intimp.2024.112580 -
Spectrochimica Acta. Part A, Molecular... Jun 2024Breast cancer (BC) is the most common malignancy among females worldwide, and its high metastasis rates are the leading cause of death just after lung cancer. Currently,...
Breast cancer (BC) is the most common malignancy among females worldwide, and its high metastasis rates are the leading cause of death just after lung cancer. Currently, tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA that has shown potential anticancer activity against BC, but the non-targeted delivery has serious side effects that limit its ubiquitous utility. Therefore, releasing anti-cancer drugs precisely to the tumor site can improve efficacy and reduce the side effects on the body. Nanotechnology has emerged as one of the most important strategies to solve the issue of overdose TAM toxicity, owing to the ability of nano-enabled formulations to deliver desirable quantity of TAM to cancer cells over a longer period of time. In view of this, use of fluorescent carbon nanoparticles in targeted drug delivery holds novel promise for improving the efficacy, safety, and specificity of TAM therapy. Here, we synthesized biocompatible carbon nanoparticles (CNPs) using chitosan molecules without any toxic surface passivating agent. Synthesized CNPs exhibit good water dispersibility and emit intense blue fluorescence upon excitation (360 nm source). The surface of the CNPs has been functionalized with folate using click chemistry to improve the targeted drug uptake by the malignant cell. The pH difference between cancer and normal cells was successfully exploited to trigger TAM release at the target site. After six hours of incubation, CNPs released ∼ 74 % of the TAM drug in acidic pH. In vitro, studies have also demonstrated that after treatment with the synthesized CNPs, significant inhibition of the tumor growth could be achieved.
PubMed: 38943755
DOI: 10.1016/j.saa.2024.124721 -
International Journal of Emergency... Jun 2024Cardiopulmonary resuscitation is a crucial skill for emergency medical services. As high-risk-low-frequency events pose an immense mental load to providers, concepts of...
BACKGROUND
Cardiopulmonary resuscitation is a crucial skill for emergency medical services. As high-risk-low-frequency events pose an immense mental load to providers, concepts of crew resource management, non-technical skills and the science of human errors are intended to prepare healthcare providers for high-pressure situations. However, medical errors occur, and organizations and institutions face the challenge of providing a blame-free error culture to achieve continuous improvement by avoiding similar errors in the future. In this case, we report a critical medical error during an anaphylaxis-associated cardiac arrest, its handling and the unexpected yet favourable outcome for the patient.
CASE PRESENTATION
During an out-of-hospital cardiac arrest due to chemotherapy-induced anaphylaxis, a patient received a 10-fold dose of epinephrine due to shortcomings in communication and standardization via a central venous port catheter. The patient converted from a non-shockable rhythm into a pulseless ventricular tachycardia and subsequently into ventricular fibrillation. The patient was cardioverted and defibrillated and had a return of spontaneous circulation with profound hypotension only 6 min after the administration of 10 mg epinephrine. The patient survived without any residues or neurological impairment.
CONCLUSIONS
This case demonstrates the potential deleterious effects of shortcomings in communication and deviation from standard protocols, especially in emergencies. Here, precise instructions, closed-loop communication and unambiguous labelling of syringes would probably have avoided the epinephrine overdose central to this case. Interestingly, this serious error may have saved the patient's life, as it led to the development of a shockable rhythm. Furthermore, as the patient was still in profound hypotension after administering 10 mg of epinephrine, this high dose might have counteracted the severe vasoplegic state in anaphylaxis-associated cardiac arrest. Lastly, as the patient was receiving care for advanced malignancy, the likelihood of termination of resuscitation in the initial non-shockable cardiac arrest was significant and possibly averted by the medication error.
PubMed: 38943049
DOI: 10.1186/s12245-024-00663-9 -
The Lancet. Public Health Jul 2024Overdose is the leading cause of death for people released from prison, and opioid agonist treatment is associated with reductions in mortality after imprisonment....
Estimated effects of opioid agonist treatment in prison on all-cause mortality and overdose mortality in people released from prison in Norway: a prospective analysis of data from the Norwegian Prison Release Study (nPRIS).
BACKGROUND
Overdose is the leading cause of death for people released from prison, and opioid agonist treatment is associated with reductions in mortality after imprisonment. However, few studies have explored the interplay of the potential modifiable risk factors and protective factors for mortality after release from prison. We aimed to describe all-cause mortality and overdose mortality among individuals released from Norwegian prisons during 2000-22 and to identify pre-existing risk factors associated with both types of mortality among these individuals for 6 months.
METHODS
For this prospective analysis, we used data from the Norwegian Prison Release Study (nPRIS), which includes all people in prison in Norway between Jan 1, 2000, and Dec 31, 2022; the Norwegian Cause of Death Registry; the Norwegian Prison Registry; the Norwegian Patient Registry; and Statistics Norway. All prisons in Norway that were open during this period were included. People who did not have a Norwegian personal identification number or were serving their sentence outside of prison units were excluded from this analysis. To identify pre-existing risk factors associated with all-cause and overdose mortality among people released from prison, we left-censored the observation period on Jan 1, 2010, creating a subsample of individuals. We calculated crude mortality rates (CMRs) and corresponding 95% CIs as the number of deaths per 100 000 person-years for several time periods after release. The primary outcomes were all-cause mortality and overdose mortality according to the ICD-10, assessed in all participants and analysed via two separate Cox proportional-hazards models.
FINDINGS
The total nPRIS cohort included 112 877 individuals released from prison in Norway between 2000 and 2022, 11 995 (10·6%) of whom were female and 100 865 (89·4%) of whom were male. We identified 13 004 instances of all-cause mortality and 3085 instances of overdose mortality during the 1 463 035 person-years. The estimated CMR for all-cause mortality was 889 (95% CI 874-904) per 100 000 person-years and for overdose mortality was 211 (203-218) per 100 000 person-years. Among people diagnosed with opioid use disorder before entering prison during 2010-22 (n=6830), provision of opioid agonist treatment was estimated to be associated with reductions in both all-cause mortality (hazard ratio 0·58, 95% CI 0·39-0·85) and overdose mortality (0·51, 0·31-0·82) in the 6 months after leaving prison after adjustment for sociodemographic, prison-related, and clinical characteristics.
INTERPRETATION
In people diagnosed with opioid use disorder released from Norwegian prisons, opioid agonist treatment provided while in prison was a protective factor for both all-cause and overdose mortality at 6 months. Provision of opioid agonist treatment while in prison is crucial in reducing mortality for 6 months after release and should be available to all people in prison who have treatment needs.
FUNDING
South-Eastern Norway Regional Health Authority and the Research Council of Norway.
Topics: Humans; Norway; Male; Prospective Studies; Female; Adult; Drug Overdose; Prisoners; Middle Aged; Cause of Death; Prisons; Risk Factors; Analgesics, Opioid; Young Adult; Mortality; Registries; Opiate Substitution Treatment; Adolescent
PubMed: 38942554
DOI: 10.1016/S2468-2667(24)00098-7 -
Annals of Epidemiology Jun 2024Opioid-involved overdoses, especially those involving synthetic opioids like fentanyl, have driven increases in overdose morbidity and mortality. Emergency medical...
BACKGROUND
Opioid-involved overdoses, especially those involving synthetic opioids like fentanyl, have driven increases in overdose morbidity and mortality. Emergency medical services (EMS) and emergency department (ED) data can each provide near real-time information on trends in nonfatal opioid-involved overdoses; however, minimal data exist on the comparability of trends in these two data sources.
METHODS
EMS data from biospatial© and ED data from CDC's Drug Overdose Surveillance and Epidemiology system and National Syndromic Surveillance Program were queried for nine states. Counts of total encounters, opioid-involved overdose encounters, and rates of opioid-involved overdoses per 10,000 total encounters were calculated for each data source from 2020-2022. Trends in monthly counts and rates were assessed using Joinpoint regression.
RESULTS
On average, EMS data captured 1.8 times more monthly opioid-involved overdose encounters than ED data. Trends in the counts of opioid-involved overdose encounters were similar in both data sources with increases and decreases occurring during roughly the same periods. Overall, trends in rates of opioid-involved overdose encounters were also comparable.
CONCLUSIONS
EMS and ED data provide complementary information for understanding overdose trends. Study findings underscore the importance of implementing post-overdose response protocols by both EMS and ED providers to ensure patient receive services irrespective of care setting.
PubMed: 38942400
DOI: 10.1016/j.annepidem.2024.06.007 -
Journal of Shoulder and Elbow Surgery Jun 2024Over-prescription of opioids in the United States increases risks of opioid dependence, overdose, and death. Increased perioperative and postoperative opioid use during...
BACKGROUND
Over-prescription of opioids in the United States increases risks of opioid dependence, overdose, and death. Increased perioperative and postoperative opioid use during orthopedic shoulder surgery is a significant risk factor for long term opioid dependence. The authors hypothesized that a multidisciplinary perioperative pain management program (Transitional Pain Service or TPS) for major shoulder surgery would lead to a reduced amount of opioids required postoperatively.
METHODS
A TPS was implemented at a Veterans Affairs Medical Center focused on non-opioid pain management and cessation support. Opioid consumption during the implementation of the TPS was compared to a historical cohort. All patients undergoing shoulder arthroplasty or rotator cuff repair were included. The primary outcome was the proportion of patients continuing opioid use at 90 days postoperatively. Secondary outcomes included postoperative pain scores, time to opioid cessation, and median opioid tablets consumed at 90-days. A multivariable model was developed to predict total opioid use at 90-days postoperatively. Kaplan Meier curves were calculated for time to opioid cessation.
RESULTS
The TPS group demonstrated decreased persistent opioid use at 90 days post-discharge (12.6% vs. 28.6%; p=0.018). Independent predictors associated with increased total opioid tablet prescriptions at 90 days included length of stay (β=19.17), anxiety diagnosis (β=37.627), and number of tablets prescribed at discharge (β=1.353). Shoulder arthroplasty surgery (TSA) was associated with decreased 90-day opioid utilization (β= -32.535) when compared to cuff repair (RCR). Median time to cessation was shorter in TSA (6 days) when compared with RCR (8 days). Pain scores were reduced compared to population mean by post-discharge day 2 for TSA and by post-discharge day 7 for RCR. Median number of post-discharge opioid tablets (oxycodone 5 mg) consumed under TPS management was 25 in both RCR and TSA surgery groups (180 MME).
DISCUSSION AND CONCLUSIONS
This study demonstrates that a TPS reduces the amount of opioid use of patients undergoing shoulder arthroplasty or cuff repair at 90 days when compared with a historical control. Multivariable regression indicated that fewer opioid tablets at discharge was a modifiable factor that may aid in reducing opioid consumption and that anxiety diagnosis, increased length of stay, and cuff repair surgery were other factors independently associated with increased opioid consumption. This data will assist surgeons in counseling patients, setting narcotic use expectations, and minimizing overprescribing. Use of a similar multidisciplinary perioperative pain management program may greatly reduce opioid over prescriptions nationally.
PubMed: 38942226
DOI: 10.1016/j.jse.2024.05.005 -
Journal of Addiction Medicine Jun 2024To prospectively assess rates of QT prolongation, arrhythmia, syncope, and sudden cardiac death (SCD) in a cohort of people with heroin dependence.
OBJECTIVES
To prospectively assess rates of QT prolongation, arrhythmia, syncope, and sudden cardiac death (SCD) in a cohort of people with heroin dependence.
METHODS
To estimate rates of QT prolongation, arrhythmia, and syncope, a subcohort (n = 130) from the Australian Treatment Outcomes Study, a prospective longitudinal cohort study of 615 people with heroin dependence, underwent medical history, venepuncture, and ECG at the 18- to 20-year follow-up.To estimate rates of SCD, probabilistic matching for the entire cohort was undertaken with the Australian Institute of Health and Welfare National Death Index. Deaths were classified into suicide, accidental overdose, trauma, unknown, and disease, which were then further subclassified by probability of SCD. SCD rate was the number of possible or probable SCDs divided by total patient years from the cohort.
RESULTS
From the subcohort, 4 participants (3%) met the criteria for QT prolongation; 3 were prescribed methadone. Seven participants (5%) reported history of arrhythmia, including 2 transferred from methadone to buprenorphine. Thirty participants (23%) reported a previous syncopal event-14 diagnosed as nonarrhythmic syncope and 13 not investigated. In the previous 12 months, 66 participants (51%) reported heroin use; 55 participants (42%) were prescribed methadone. No participant had QTc greater than 500 milliseconds.There were 3 possible SCDs, translating to an estimated SCD rate of 0.29 (CI: 0.05, 0.8) events per 1000 patient years. More cohort members died of overdose (n = 50), suicide (n = 11), and hepatitis C (n = 4).
CONCLUSIONS
Low rates of QT prolongation, arrhythmia, syncope, and SCD in the cohort despite high rates of heroin use and methadone treatment.
PubMed: 38941157
DOI: 10.1097/ADM.0000000000001317