Central Nervous System Agents Research Articles

Zika virus and brain cancer: Can Zika be an effective treatment for brain cancer? A systematic review.

Many studies have highlighted the use of oncolytic viruses as a new class of therapeutic agents for central nervous system (CNS) tumors, especially glioblastomas (GMB). Zika Virus (ZIKV) proteins targeted to specific stem cells have been studied in vitro and animal models with promising results. A systematic review was evaluated the efficacy and safety of the ZIKV use for CNS tumors treatment. Data were extracted and the in vivo studies were evaluated using the Robins-I tool. We assessed bias in each study using criteria such as selection bias, performance bias, detection bias, attrition bias, reporting bias, and others. According to Cochrane guidelines, bias was classified as high, low, or uncertain. High bias occurred when studies did not meet the criteria. Low bias was assigned when criteria were clearly met. Uncertain bias reflected insufficient information for a clear classification. The 14 included studies shown that ZIKV reduced cell viability or inhibited the growth, proliferation of glioma stem cells (GSCs), and Bcl2 expression - which could potentially enhance the effect of chemotherapy/radiotherapy; caused cytopathic effects, induced tumor cell damage, manifested oncolytic properties, and even selectively safely killed GSCs; ultimately, it led to significant tumor remission and enhanced long-term survival through enhanced T-cell response. Although current evidence suggests ZIKV as a promising treatment for CNS tumors and may improve survival when combined with surgery and radiotherapy. Despite limited human evidence, it shows potential benefits. Further research is needed to confirm safety, efficacy, and optimize treatment in humans.

Age-related differences in drug-induced liver injury: a retrospective single-center study from a large liver disease specialty hospital in China, 2002–2022

Background and aimsDrug-induced liver injury (DILI) is a prevalent adverse reaction in clinical settings. However, there is limited research on age-related differences in DILI. We performed a large-scale retrospective study to delineate the characteristics of DILI across different age groups.MethodsWe collected data on a total of 17,946 patients with confirmed DILI hospitalized at the Fifth Medical Center of the People’s Liberation Army (PLA) General Hospital in Beijing, China, from January 1, 2002, to December 31, 2022. The patients were stratified based on age into the following groups: children (< 18 years), young adults (18–44 years), middle-aged individuals (45–64 years), and elderly individuals (≥ 65 years). We gathered demographic information, medical histories, laboratory results, disease severity assessments, and mortality statistics for all patients.ResultsOverall, the distribution of DILI cases across different age groups was as follows: 6.57% were children, 24.82% were young adults, 49.06% were middle-aged individuals, and 19.54% were elderly individuals. The percentage of females increased with age, rising from 36.47% in the pediatric group to 60.51% in the elderly group. Notably, central nervous system agents (15.44%) and anti-infectious agents (21.80%) were more commonly associated with DILI in children, while cardiovascular agents (10.58%) and herbal dietary supplements or traditional medicines (H/TMs) (26.29%) were more prevalent among elderly people with DILI. Among all age groups, hepatocellular-type DILI was more common in the pediatric group (p < 0.001), whereas cholestatic-type DILI and chronic DILI were more prevalent in the elderly group (p < 0.001). Acute liver failure (ALF) and fatal outcomes were more prevalent in the pediatric and elderly groups, particularly in the pediatric group (2.04%, p = 0.041; 0.85%, p = 0.007, respectively).ConclusionsChildren and elderly individuals face a higher risk of adverse outcomes following DILI.Graphical

Tramadol use in U.S. Adults With Commercial Health Insurance, 2005–2021

IntroductionTramadol has been associated with chronic opioid use and emergency room (ER) visits. However, little is known about trends in prescription tramadol use in the US. MethodsOptum's de-identified Clinformatics® Data Mart Database was used to assess trends in monthly incident and prevalent tramadol use from 2005 to 2021, stratified by sex and age (18-64 vs. ≥65 years). State-specific trends following scheduling of tramadol as Class IV controlled substance in August 2014 were analyzed with random effects regression models. Demographics, comorbidities, initiation setting, dose, and co-dispensing with other opioids and central nervous system (CNS) agents were assessed in people initiating tramadol, stratified by age and initiation year (2005-2010, 2011-2015, 2016-2021). Analyses were performed in 2023 and 2024. ResultsDuring 2005-2021, the mean percentage using tramadol in a given month was 0.88% of younger females, 0.55% of younger males, 1.97% of older females, and 1.14% of older males; 5,729,652 initiations were identified. Since 2014, estimated relative yearly decrease was 4% (95% CI 3%; 5%) in use and 5% (95% CI 4%; 5%) in initiation, with variation across states. Primary care percentage of tramadol initiations declined from 49.2% in 2005-2010 to 37.2% in 2016-2021. During 2016-2021, co-dispensing with other CNS agents occurred in 37.8% of younger and 32.1% of older adults initiating tramadol. ConclusionsTramadol use was higher in females and older adults, exhibited heterogeneous trends across states, and shifted from primary care to ER and specialist settings over time. Co-dispensing with other CNS agents was common and warrants further monitoring.

Selective Uptake of Macromolecules to the Brain in Microfluidics and Animal Models Using the HAVN1 Peptide as a Blood-Brain Barrier Modulator.

Monoclonal antibodies (mAbs) possess favorable pharmacokinetic properties, high binding specificity and affinity, and minimal off-target effects, making them promising therapeutic agents for central nervous system (CNS) disorders. However, their development as effective therapeutic and diagnostic agents for brain disorders is hindered by their limited ability to efficiently penetrate the blood-brain barrier (BBB). Therefore, it is crucial to develop efficient delivery methods that enhance the penetration of antibodies into the brain. Previous studies have demonstrated the potential of cadherin-derived peptides (i.e., ADTC5, HAVN1 peptides) as BBB modulators (BBBMs) to increase paracellular porosities for penetration of molecules across the BBB. Here, we test the effectiveness of the leading BBBM peptide, HAVN1 (Cyclo(1,6)SHAVSS), in enhancing the permeation of various monoclonal antibodies through the BBB using both in vitro and in vivo systems. In vitro, HAVN1 has been shown to increase the permeability of fluorescently labeled macromolecules, such as a 70 kDa dextran, 50 kDa Fab1, and 150 kDa mAb1, by 4- to 9-fold in a three-dimensional blood-brain barrier (3D-BBB) microfluidics model using a human BBB endothelial cell line (i.e., hCMEC/D3). HAVN1 was selective in modulating the BBB endothelial cell, compared to the pulmonary vascular endothelial (PVE) cell barrier. Co-administration of HAVN1 significantly improved brain depositions of mAb1, mAb2, and Fab1 in C57BL/6 mice after 15 min in the systemic circulation. Furthermore, HAVN1 still significantly enhanced brain deposition of mAb2 when it was administered 24 h after the administration of the mAb. Lastly, we observed that multiple doses of HAVN1 may have a cumulative effect on the brain deposition of mAb2 within a 24-h period. These findings offer promising insights into optimizing HAVN1 and mAb dosing regimens to control or modulate mAb brain deposition for achieving desired mAb dose in the brain to provide its therapeutic effects.

The integrated stress response-related expression of CHOP due to mitochondrial toxicity is a warning sign for DILI liability.

Drug-induced liver injury (DILI) is one of the most frequent reasons for failure of drugs in clinical trials or market withdrawal. Early assessment of DILI risk remains a major challenge during drug development. Here, we present a mechanism-based weight-of-evidence approach able to identify certain candidate compounds with DILI liabilities due to mitochondrial toxicity. A total of 1587 FDA-approved drugs and 378 kinase inhibitors were screened for cellular stress response activation associated with DILI using an imaging-based HepG2 BAC-GFP reporter platform including the integrated stress response (CHOP), DNA damage response (P21) and oxidative stress response (SRXN1). In total 389, 219 and 104 drugs were able to induce CHOP-GFP, P21-GFP and SRXN1-GFP expression at 50 μM respectively. Concentration response analysis identified 154 FDA-approved drugs as critical CHOP-GFP inducers. Based on predicted and observed (pre-)clinical DILI liabilities of these drugs, nine antimycotic drugs (e.g. butoconazole, miconazole, tioconazole) and 13 central nervous system (CNS) agents (e.g. duloxetine, fluoxetine) were selected for transcriptomic evaluation using whole-genome RNA-sequencing of primary human hepatocytes. Gene network analysis uncovered mitochondrial processes, NRF2 signalling and xenobiotic metabolism as most affected by the antimycotic drugs and CNS agents. Both the selected antimycotics and CNS agents caused impairment of mitochondrial oxygen consumption in both HepG2 and primary human hepatocytes. Together, the results suggest that early pre-clinical screening for CHOP expression could indicate liability of mitochondrial toxicity in the context of DILI, and, therefore, could serve as an important warning signal to consider during decision-making in drug development.

An in-silico investigation based on molecular simulations of novel and potential brain-penetrant GluN2B NMDA receptor antagonists as anti-stroke therapeutic agents

GluN2B-induced activation of NMDA receptors plays a key function in central nervous system (CNS) disorders, including Parkinson, Alzheimer, and stroke, as it is strongly involved in excitotoxicity, which makes selective NMDA receptor antagonists one of the potential therapeutic agents for the treatment of neurodegenerative diseases, especially stroke. The present study aims to examine a structural family of thirty brain-penetrating GluN2B N-methyl-D-aspartate (NMDA) receptor antagonists, using virtual computer-assisted drug design (CADD) to discover highly candidate drugs for ischemic strokes. Initially, the physicochemical and ADMET pharmacokinetic properties confirmed that C13 and C22 compounds were predicted as non-toxic inhibitors of CYP2D6 and CYP3A4 cytochromes, with human intestinal absorption (HIA) exceeding 90%, and designed to be as efficient central nervous system (CNS) agents due to the highest probability to cross the blood-brain barrier (BBB). Compared to ifenprodil, a co-crystallized ligand complexed with the transport protein encoded as 3QEL.pdb, we have noticed that C13 and C22 chemical compounds were defined by good ADME-Toxicity profiles, meeting Lipinski, Veber, Egan, Ghose, and Muegge rules. The molecular docking results indicated that C22 and C13 ligands react specifically with the amino acid residues of the NMDA receptor subunit GluN1 and GluN2B. These intermolecular interactions produced between the candidate drugs and the targeted protein in the B chain remain stable over 200 nanoseconds of molecular dynamics simulation time. In conclusion, C22 and C13 ligands are highly recommended as anti-stroke therapeutic drugs due to their safety and molecular stability towards NMDA receptors. Communicated by Ramaswamy H. Sarma

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier.

Drug development for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease has challenging difficulties due to the pharmacokinetic impermeability based on the blood-brain barrier (BBB) as well as the blurriness of pharmacodynamic targets based on their unclarified pathogenesis and complicated progression mechanisms. Thus, in order to produce innovative central nervous system (CNS) agents for patients suffering from CNS diseases, effective, selective delivery of CNS agents into the brain across the BBB should be developed. Currently, proteolysis-targeting chimeras (PROTACs) attract rising attention as a new modality to degrade arbitrary intracellular proteins by the ubiquitin-proteasome system. The internalizations of peptide-based PROTACs by cell-penetrating peptides and that of small molecule-based PROTACs through passive diffusion lack cell selectivity. Therefore, these approaches may bring off-target side effects due to wrong distribution. Furthermore, efflux transporters such as multiple drug resistance 1 (MDR1) expressed at the BBB might interrupt the entry of small molecule-based PROTACs into the brain. Nonetheless, intelligent delivery using machinery systems to absorb the nutrition into the brain for homeostasis, such as carrier-mediated transport (CMT) or receptor-mediated transcytosis (RMT), can be established. PROTACs with N-containing groups that are recognized by the proton-coupled organic cation antiporter might cross the BBB through CMT. PROTAC-antibody conjugates (PACs) might cross the BBB through RMT. Subsequently, such small molecule-based PROTACs released in the brain interstitial fluid would be transported into cells such as neurons through passive diffusion and then demonstrate arbitrary protein degradation. In this review, I introduce the potential and advantages of PROTAC delivery into the brain across the BBB through CMT or RMT using PACs in a non-invasive way.

Nighttime medication administration and patient perception of sleep in the intensive care unit

AbstractIntroductionEnvironmental, patient, disease, and care‐related factors can lead to sleep disruption in the intensive care unit (ICU). Medication administration is a potentially modifiable factor in this setting that has not been well described as a target for sleep improvement.ObjectivesTo determine characteristics of nighttime medication administration practices in the ICU, evaluate the effect on patient perceived sleep, and assess the opportunity for pharmacist‐led nighttime medication administration stewardship.MethodsThis was a multicenter, retrospective, observational cohort study. Patients included for chart review had perceived sleep measured using the Richards‐Campbell Sleep Questionnaire (RCSQ). Data were collected on patient characteristics, ICU exposures, and nighttime medications administered. Four RCSQ groups defined for comparison were RCSQ 0–25 indicating “very poor” sleep, 26–50 “poor” sleep, 51–75 “good” sleep, and 76–100 “very good” sleep.ResultsOverall, 115 patients with RCSQ assessments and 435 nighttime medication administrations were included. Nighttime medications were most commonly cardiovascular (28.9%) and central nervous system (21.4%) agents, administered via intravenous (54.5%) and oral (22.7%) routes. Patient characteristics were comparable between the four groups except for history of head trauma. Patients reporting very poor sleep had a significantly higher median number of nighttime medications administered as compared to patients reporting very good sleep (4.0 [interquartile range (IQR) (2, 6)] vs. 2.5 [IQR 1, 4], adjusted p = 0.048). Approximately three‐quarters of nighttime medications occurred between the hours of 22:00–0:59 and 5:00–5:59. Nearly 40% of nighttime medications could have been retimed for daytime administration.ConclusionsUnnecessary nighttime medication administration is common and associated with poor patient perceived sleep in the ICU. Pharmacists are well‐positioned to evaluate timing of medication administration and cluster medication‐related care for daytime hours, when appropriate. Nighttime medication stewardship optimization by pharmacists is an opportunity to improve patient perceived sleep in the ICU.

Variations in sociodemographic and health-related factors are linked to distinct clusters of individuals with depression based on the PHQ-9 instrument: NHANES 2007–2018

BackgroundDepression is a heterogeneous disease. Identification of latent depression subgroups and differential associations across these putative groups and sociodemographic and health-related factors might pave the way toward targeted treatment of individuals. MethodsWe used model-based clustering to identify relevant subgroups of 2900 individuals with moderate to severe depression (defined as scores ≥10 on the PHQ-9 instrument) from the NHANES cross-sectional survey. We used ANOVA and chi-squared tests to assess associations between cluster membership and sociodemographics, health-related variables, and prescription medication use. ResultsWe identified six latent clusters of individuals, three based on depression severity and three differentially loaded by somatic and mental components of the PHQ-9. The Severe mental depression cluster had the most individuals with low education and income (P < 0.05). We observed differences in the prevalence of numerous health conditions, with the Severe mental depression cluster showing the worst overall physical health. We observed marked differences between the clusters regarding prescription medication use: the Severe mental depression cluster had the highest use of cardiovascular and metabolic agents, while the Uniform severe depression cluster showed the highest use of central nervous system and psychotherapeutic agents. LimitationsDue to the cross-sectional design we cannot make conclusions about causal relationships. We used self-reported data. We did not have access to a replication cohort. ConclusionsWe show that socioeconomic factors, somatic diseases, and prescription medication use are differentially associated with distinct and clinically relevant clusters of individuals with moderate to severe depression.

Determination of Clomipramine using eco-friendly solid-contact ionophore-doped potentiometric sensor

IntroductionClomipramine is a tricyclic antidepressant acting as a serotonin reuptake inhibitor. Its maximum plasma concentration (Cmax) is 13–310 ng/mL, the therapeutic range is 220–500 ng/mL and its toxic effect appears in doses above 900 ng/mL.ObjectivesThe fabrication of eco-friendly solid-contact ion-selective electrodes to evaluate the concentration of Clomipramine in different matrices based on disposable screen-printed carbon electrode.MethodsDisposable screen-printed carbon electrode was utilized as a substrate to fabricate the proposed sensors. The sensors were optimized to determine Clomipramine using calix[4]arene as an ionophore into PVC polymeric membrane to enhance selectivity towards the target analyte. The solid-contact sensor potential stability was improved by the incorporation of graphene nanoparticles transducer layer.ResultsThe sensors were assessed as per the IUPAC recommendations. The linearity range was 1 × 10− 2 to 1 × 10− 5.3 M. The sensors were successfully applied to determine CLM in the pharmaceutical formulation. Furthermore, the ion selective electrodes were applied for Clompiramine assay in spiked plasma for the purpose of Point-of-Care testing to be a diagnostic tool for therapeutic monitoring of the cited central nervous system agent. The findings were statistically compared to the reported method showing no statistically significant difference.ConclusionThis work was concerned with developing a green analytical method for the determination of Clomipramine. The proposed SC-ISE was mixed with graphene nanocomposite transducer interlayer. The graphene layer succeeded in preventing the formation of an aqueous layer so resulted in a stable, reproducible standard potential besides the rapid response time.

Cytotoxicity and internalization properties of novel alpha7 nicotinic receptor selective peptides.

Cell-penetrating peptides (CPPs) contain ≤30 residues and have the unique ability to enter cells, making them attractive agents for Central Nervous System (CNS)-targeted drug delivery. Examples are CPPs derived from the rabies virus glycoprotein (RVG). RVG-derived peptides make use of a nicotinic acetylcholine receptor (nAChR)-mediated mechanism to enter the mouse CNS and deliver cargo. However, previously developed RVG-derived peptides lack selectivity for distinct nAChR subtypes, which are associated with different neurological diseases. As an example, dysregulation of the homomeric α7-nAChR is involved in Alzheimer's disease and depression. In an effort to develop an α7-nAChR-selective CPP, we hypothesized that combining regions of the RVG with those of a protein known to specifically interact with the α7-nAChR subtype could create a chimeric peptide with CPP properties that is α7-nAChR selective. However, insertion of protein segments into RVG brings possibility for altering cytotoxic and cell internalization properties. To investigate these changes for our RVG-chimeric peptides, we cultured and transfected neuronal-like cells with α7 subunits and the nAChR chaperone NACHO, and verified expression using fluorescent tags. We treated cells with RVG or fusion peptides using a range of concentrations to obtain their cytotoxic profiles using a redox indicator for cell viability. Separately, α7-nAChR cells were treated with the lead peptide containing the fluorescent tag FITC and visualized using live cell confocal fluorescence microscopy. We did not observe significant cytotoxic effects of the original RVG or chimeric peptides for concentrations ranging from 0.3 nM to 100 μM. Additionally, our data suggests that the lead chimeric peptide can enter neuronal-like cells by using an α7-nAChR-mediated mechanism. An α7-nAChR subtype-selective therapeutic agent has the potential to aid in depression treatment, without creating unwanted off-target effects. Moreover, it may be useful as vehicle for CNS-targeted drug delivery.

Fingolimod increases parvalbumin-positive neurons in adult mice.

In recent years, it has been shown that central nervous system agents, such as antidepressants and antiepileptic drugs, reopen a critical period in mature animals. Fingolimod, which is used for the treatment of multiple sclerosis, also restores neuroplasticity. In this study, we investigated the effects of parvalbumin (PV)-positive neurons and perineuronal nets (PNN) on fingolimod administration with respect to neuroplasticity. Fingolimod was chronically administered intraperitoneally to mature mice. PV-positive neurons and PNN in the hippocampus, prefrontal cortex, and somatosensory cortex were analyzed. An increase in PV-positive neurons was observed in the hippocampus, prefrontal cortex, and somatosensory cortex of the fingolimod-treated mice. An increase in Wisteria floribunda agglutinin-positive PNN was confirmed in mice treated with fingolimod in the somatosensory cortex only. Fingolimod increased the density of PV-positive neurons in the brains of mature mice. The results indicate that fingolimod may change the critical period in mature animals.

CFT7455, a Novel IKZF1/3 Degrader, Demonstrates Potent Anti-Tumor Activity in Models of Non-Hodgkin's Lymphoma As a Single Agent or in Combination with Clinically Approved Agents

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL). These drugs induce an interaction between Ikaros family zinc finger proteins 1 and 3 (IKZF1/3) and cereblon (CRBN), an E3 ligase, resulting in IKZF1/3 degradation. IKZF1/3 are master transcription factors that play a key role in B and T-cell differentiation and maintain levels of interferon regulatory factor 4 (IRF4), a critical regulator in NHL. Clinically, immunomodulatory drugs have shown activity as single agents and when used in combination with several classes of targeted therapies, such as rituximab, in both first line and relapsed/refractory NHL subtypes. We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-1600-fold increased potency over pomalidomide in CRBN binding and cellular IKZF1 degradation assays. We demonstrated that this increased activity translated into dramatically greater efficacy compared to pomalidomide in cellular and in vivo preclinical models of multiple myeloma and NHL. Here we show that the increased catalytic activity and improved potency of CFT7455 also translates into potent anti-tumor activity as single agent or in combination with clinically approved agents in central nervous system (CNS) and subcutaneous models of NHL. In both the Raji and OCI-Ly10 CNS xenograft models, CFT7455 (100 µg/kg/day) led to a significant increase in survival in comparison to pomalidomide (P=0.002, P=0.0002). The combination of immunomodulatory drugs with CD20, BTK, or HDAC targeting agents shows promising clinical activity in the treatment of NHL. Combination studies were conducted, dosing CFT7455 in combination with rituximab, ibrutinib, or the HDAC inhibitor romidepsin in several models of NHL. In the mantle cell lymphoma (MCL) model, Mino, the combination of CFT7455 with rituximab demonstrated synergistic activity and complete tumor regression. In the diffuse large B-cell lymphoma (DLBCL) model, TMD8, the combination of ibrutinib and CFT7455 was synergistic and resulted in a significant increase in survival probability. In the CNS NHL model, OCI-Ly10, the combination of CFT7455 with rituximab or ibrutinib also led to a significant increase in survival probability highlighting the therapeutic potential of this combination. Synergistic activity was also observed with the combination of CFT7455 and romidepsin in two models of anaplastic large cell lymphoma (ALCL). In conclusion, CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent and combination antitumor activity in DLBCL, ALCL, and MCL models, supporting clinical investigation of CFT7455 for NHL.

Prescription medication use of United States military service members by therapeutic classification.

Background: This cross-sectional study investigated the prevalence of, and factors associated with, filled prescription medications (FPMs) among United States (US) service members (SMs). Methods: A stratified random sample of active duty SMs from the Air Force, Army, Marine Corps, and Navy was obtained from military workforce records. Participants (n = 26,680) completed a questionnaire on demographics, physical characteristics, and lifestyle factors and approved access to their FPM for the previous 6 months. FPMs were obtained from the military Pharmacy Data Transaction Service that included all prescription medications dispensed at military medical treatment facilities, abroad, at retail pharmacies in the US, and/or through mail-order programs. Results: About two-thirds (65%) of SMs had ≥1 FPM in the 6 months surveillance period. Central nervous system (CNS) agents had the highest prevalence (41%), followed by anti-infective agents (20%), eye/ear/nose/throat preparations (20%), gastrointestinal drugs (18%), autonomic drugs (17%), skin and mucous membrane agents (13%), antihistamine drugs (12%), respiratory tract agents (12%) and cardiovascular drugs (9%). Among CNS agents, overall prevalence of dispensed non-steroidal anti-inflammatory drug (NSAIDs) was 30%. The odds of any FPM was independently associated with female gender, older age, higher body mass index, former tobacco use (smoking and smokeless tobacco), lower alcohol consumption, and was highest among Army, lowest among Marine Corps personnel. Conclusion: In this sample of SMs, dispensing of prescription medication was high, especially NSAIDs, but dispensing of cardiovascular drugs was much lower compared to the general US population, likely because of the younger age and higher level of physical activity of SMs.

Poisoning in older adults: characterization of exposures reported to the Dutch Poisons Information Center

Introduction: The annual number of patients > 65 years old about whom the Dutch Poisons Information Center (DPIC) was consulted has more than doubled in the last decade. We aimed to gain insight in the type and circumstances of exposures reported to the DPIC involving older patients, in order to help prevent future poisonings. Methods: Enquiries to the DPIC involving patients > 65 years old were prospectively included from January 2019 to June 2019. Data were collected on patient characteristics (e.g., age, gender, and living situation) and exposure characteristics (e.g., type and exposure scenario). Results: In the first half of 2019, the DPIC was consulted about 1051 patients > 65 years old. The median age of the patients was 77 years old (range: 66–104 years) and women were over-represented (61%). A total of 1650 different substances were reported, 1213 pharmaceutical exposures (74%) and 437 non-pharmaceutical exposures (26%), mostly household products (n = 162). Most pharmaceutical exposures involved cardiovascular agents (n = 367, 30%), central and peripheral nervous system agents (n = 354, 29%), and analgesics (n = 152, 13%). In 71% of the patients exposed to pharmaceuticals, the drugs were taken unintentionally (n = 471), frequently caused by medication errors made by the patients themselves (n = 357, 76%). Most common scenarios included inadvertently taken/given a double (n = 140, 30%) or more than double (n = 94, 20%) dose or the wrong medication (n = 124, 26%). The most common scenario for unintentional exposure to non-pharmaceuticals was “mistook product for food/drink” (n = 122, 37%). Conclusions: The majority of intoxications in older adults are accidental and often involve medication errors. Unintentional poisoning is often preventable. If patients are cognitively impaired, potentially harmful substances should be kept out of their reach and medication should only be administered under direct supervision. Clear labelling, simplified drug regimens and the use of automatic medication dispensers could reduce the risk of medication errors in older patients.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

US drug shortages compared to the World Health Organization's Model List of Essential Medicines for Children: A cross-sectional study.

To describe US drug shortages affecting medications on the 2019 World Health Organization (WHO) Model List of Essential Medicines for Children (EMLc). Drug shortage data from January 2014 to December 2019 were obtained from the University of Utah Drug Information Service. Shortage data for drugs on the EMLc were analyzed for the type of drug, American Hospital Formulary Service category, reason for the shortage, duration of the shortage, marketing status (generic vs brand name), and whether the agent was a single- or multisource drug. From 2014 to 2019, a total of 209 drug shortages impacted medications on the EMLc, of which 77 (36.8%) remained unresolved by 2019. Of all active shortages, 13 (6.2%) began before 2014. Resolved shortages had a median duration of 5.9 months (interquartile range [IQR], 3.6-13.2 months) while active shortages had a median duration of 18.3 months (IQR, 10.9-33.5 months; P ≤ 0.0001). The therapeutic categories most impacted by drug shortages were anti-infective agents (27.3%), central nervous system agents (12.9%), and antineoplastic agents (11.0%). The reason for the shortage was not reported in 46.4% of cases. When a reason was provided, the most common reason was manufacturing problems (29.2%) followed by supply/demand mismatch (15.8%). US drug shortages affected many medications on the WHO EMLc. Future studies should examine the global shortage climate and implications for patient care.

Investigation of the Etiological Causes of Central Nervous System Infection in Children with Multiplex PCR

Objective The aim of this study is to investigate the causative agents of central nervous system (CNS) infection in hospitalized pediatric patients by multiplex polymerase chain reaction. Methods We retrospectively reviewed the medical records of children who underwent lumbar puncture with suspected CNS infection between September 2019 and September 2021. The cerebrospinal fluid (CSF) samples were evaluated by the BioFire FilmArray Meningitis/Encephalitis (ME) Panel. Results The etiology of the infection was established in 13,02% (n = 25) cases. Human herpesvirus (HHV) type 6 was the most commonly identified pathogen 60% (n = 15), followed by enterovirus 20% (n = 5), Streptococcus pneumoniae 8% (n = 2), Streptococcus agalactiae 4% (n = 1), HHV type 1 4% (n = 1), and Listeria monocytogenes 4% (n = 1). The statistical analysis showed that the age of the group with enterovirus was younger than the age of the group with other causative microorganisms and the group with HHV-6 (respectively p: 0.032; p: 0.011). The hospitalization periods of the group with enterovirus and HHV-6 were shorter than the hospitalization periods of the other causative microorganisms (respectively p: 0.016; p: 0.000) and the absolute neutrophil count values of the group with HHV-6 were lower than the group of other causative microorganisms (p: 0.015). Conclusion Our study identified HHV-6 as the main cause of CNS infection in Istanbul during coronavirus disease 2019 pandemic when isolation measures were taken. The duration of hospital stay was found to be shorter in CNS infection caused by viral agents. Revealing the causative agent in the CSF is a fast and effective method that prevents unnecessary antibiotic treatment and shortens the hospitalization period of patients.

Prescription medication use and trends for U.S. Navy submariners from 2007 to 2018

Introduction: This is the first study to examine population medication prescription rates among U.S. submariners by common therapeutic classifications. Methods: Individual-level pharmacy records during the years 2007 to 2018 were extracted from the Military Health System’s Pharmacy Data Transaction Service (PDTS) file. Demographic and military factors captured from Navy personnel files were linked to PDTS records. Logistic regression models were used to identify characteristics and trends associated with prevalence. Published total rates for other active-duty components were compared to submariner rates. Results: There were data for 50,720 submariners, among whom 576,782 prescriptions were filled. Prevalence rates decreased significantly from 2007-2018 among most drug classes. Central nervous system agents accounted for 31% of the total prescriptions, followed by 12% for eye, ear, nose, and throat preparations, and 10% for anti-infective agents. Higher prescription rates were associated with being enlisted, younger, a woman, lower-ranked, or Hispanic. The mean yearly prescription rate was 2.7 per submariner, less than half of the overall rate of all military components. Conclusions: Central nervous system agents were the most common drug class for submariners and all military components. Future work at the drug level is warranted to better understand the temporal declines in submariner rates and if submariner rates are lower than overall active-duty rates due to health status measures, sex, or allowance guidelines. Drug-level utilization can help determine if onboard medications should be adjusted to meet the current needs of men, and the needs of the growing submariner population of women.

Patient-Level Fall Risk Prediction Using the Observational Medical Outcomes Partnership's Common Data Model: Pilot Feasibility Study.

BackgroundFalls in acute care settings threaten patients’ safety. Researchers have been developing fall risk prediction models and exploring risk factors to provide evidence-based fall prevention practices; however, such efforts are hindered by insufficient samples, limited covariates, and a lack of standardized methodologies that aid study replication.ObjectiveThe objectives of this study were to (1) convert fall-related electronic health record data into the standardized Observational Medical Outcome Partnership's (OMOP) common data model format and (2) develop models that predict fall risk during 2 time periods.MethodsAs a pilot feasibility test, we converted fall-related electronic health record data (nursing notes, fall risk assessment sheet, patient acuity assessment sheet, and clinical observation sheet) into standardized OMOP common data model format using an extraction, transformation, and load process. We developed fall risk prediction models for 2 time periods (within 7 days of admission and during the entire hospital stay) using 2 algorithms (least absolute shrinkage and selection operator logistic regression and random forest).ResultsIn total, 6277 nursing statements, 747,049,486 clinical observation sheet records, 1,554,775 fall risk scores, and 5,685,011 patient acuity scores were converted into OMOP common data model format. All our models (area under the receiver operating characteristic curve 0.692-0.726) performed better than the Hendrich II Fall Risk Model. Patient acuity score, fall history, age ≥60 years, movement disorder, and central nervous system agents were the most important predictors in the logistic regression models.ConclusionsTo enhance model performance further, we are currently converting all nursing records into the OMOP common data model data format, which will then be included in the models. Thus, in the near future, the performance of fall risk prediction models could be improved through the application of abundant nursing records and external validation.