Bioessays. 2023 Dec 7:e2300117. doi: 10.1002/bies.202300117. Online ahead of print.

ABSTRACT

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

PMID:38059881 | DOI:10.1002/bies.202300117

ANZ J Surg. 2023 Dec 7. doi: 10.1111/ans.18812. Online ahead of print.

ABSTRACT

BACKGROUND: In recent years, certain body composition measures, assessed by computed tomography (CT), have been found to be associated with chemotherapy toxicities. This review aims to explore available data on the relationship between skeletal muscle and adiposity, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intramuscular and intermuscular adipose tissue and their association with chemotherapy toxicity in non-metastatic colorectal cancer (CRC) patients.

METHODS: A systematic literature search following PRISMA guidelines was conducted in Medline, Embase, Cochrane and Web of Science, for papers published between 2011 and 2023. The search strategy combined keywords and MESH terms relevant to 'body composition', 'chemotherapy toxicities', and 'non-metastatic colorectal cancer'.

RESULTS: Out of 3868 studies identified, six retrospective studies fulfilled the inclusion criteria with 1024 eligible patients. Low skeletal muscle mass was strongly associated with increased incidence of both chemotherapy toxicities and dose-limiting toxicity (DLT). The association of VAT, intramuscular and intermuscular adiposity was heterogeneous and inconclusive. There was no association between SAT and chemotherapy intolerance. No universal definitions or cut-offs for sarcopenia and obesity were noted. All studies utilized 2-dimensional (2D) CT slices for CT body composition assessment with varied selection on the vertebral landmark and inconsistent reporting of tissue-defining Hounsfield unit (HU) measurements.

CONCLUSION: Low skeletal muscle is associated with chemotherapy toxicities in non-metastatic CRC. However, quality evidence on the role of adiposity is limited and heterogeneous. More studies are needed to confirm these associations with an emphasis on a more coherent body composition definition and an approach to its assessment, especially regarding sarcopenia.

PMID:38059530 | DOI:10.1111/ans.18812

Case Rep Ophthalmol. 2023 Dec 5;14(1):673-678. doi: 10.1159/000535077. eCollection 2023 Jan-Dec.

ABSTRACT

INTRODUCTION: With the increasing use of immune checkpoint inhibitors, ocular adverse events have gained attention. We describe a case of atypical keratitis presumably induced by atezolizumab, a programmed cell death ligand 1 inhibitor.

CASE PRESENTATION: A 73-year-old Japanese woman developed ring-shaped marginal infiltrations with epithelial breakdown of the corneas in both eyes. The patient had advanced small cell lung cancer and had received intravenous carboplatin, etoposide, and atezolizumab. She was treated with topical administration of 0.1% sodium phosphate betamethasone and 0.5% moxifloxacin six times daily. On day 14 following initial presentation, marked reduction of bilateral corneal infiltration was observed. During the succeeding cycles of chemotherapy, marginal keratitis did not recur, and then, the topical steroid was gradually tapered.

CONCLUSIONS: Cancer immunotherapy, including atezolizumab, may lead to active T-cell recruitment into the cornea, which result in autoimmune corneal keratitis. We believe that this report is informative to both ophthalmologists and oncologists involved in the treatment of patients receiving cancer immunotherapy.

PMID:38058358 | PMC:PMC10697742 | DOI:10.1159/000535077

Clin Nutr ESPEN. 2023 Dec;58:152-159. doi: 10.1016/j.clnesp.2023.09.919. Epub 2023 Sep 24.

ABSTRACT

BACKGROUND & AIMS: The concurrent use of herbal and dietary supplements and conventional drugs can lead to interactions in patients with cancer, of which hepatotoxicity is one of the most concerning sequelae. This study examined the potential supplement-drug interactions involving the hepatic system, and their associations with documented liver diseases, among patients with cancer in a large population-based cohort in the UK Biobank.

METHODS: Participants diagnosed with cancer and had completed supplement-use assessment after diagnosis were included. Potentially interacting supplement-drug combinations that involved CYP enzymes or increased the risk of hepatotoxicity were identified from four tertiary databases. Liver diseases were identified using ICD-codes K70-77. Log-binomial regression was used to investigate the associations between potentially-interacting supplement-drug combinations and liver diseases documented (1) at any time, and (2) confined to only after the time of supplement-use assessment, adjusting for age, sex and pre-existing comorbidities.

RESULTS: This analysis included 30,239 participants (mean age = 60.0 years; 61.9% female). Over half (n = 17,698, 58.5%) reported the use of supplements after cancer diagnoses. Among supplements users, 36.9% (n = 6537/17,698) were on supplement-drug combinations with interacting potential involving the hepatic system. Patients taking supplements and drugs who had hepatic comorbidities were more likely to take potentially interacting pairs (adjusted risk ratio = 1.14, 95% CI = 1.06-1.23, p < 0.001). However, no significant association was observed between the use of these combinations and subsequent liver diseases (all p > 0.05).

CONCLUSION: Approximately one-third of the participants who had cancer and were supplement users had a risk of potential supplement-drug interactions that contribute to adverse liver effect. Healthcare professionals should communicate with patients with cancer, especially those with pre-existing liver diseases, about supplement use and proactively assess the clinical significance of potential interactions.

PMID:38057000 | DOI:10.1016/j.clnesp.2023.09.919

J Med Syst. 2023 Dec 6;48(1):2. doi: 10.1007/s10916-023-02008-0.

ABSTRACT

The development of health information technology available and accessible to professionals is increasing in the last few years. However, a low number of electronic health tools included some kind of information about medication reconciliation. To identify all the electronic medication reconciliation tools aimed at healthcare professionals and summarize their main features, availability, and clinical impact on patient safety. A systematic review of studies that included a description of an electronic medication reconciliation tool (web-based or mobile app) aimed at healthcare professionals was conducted. The review protocol was registered with PROSPERO: registration number CRD42022366662, and followed PRISMA guidelines. The literature search was performed using four healthcare databases: PubMed, EMBASE, Cochrane Library, and Scopus with no language or publication date restrictions. We identified a total of 1227 articles, of which only 12 met the inclusion criteria.Through these articles,12 electronic tools were detected. Viewing and comparing different medication lists and grouping medications into multiple categories were some of the more recurring features of the tools. With respect to the clinical impact on patient safety, a reduction in adverse drug events or medication discrepancies was detected in up to four tools, but no significant differences in emergency room visits or hospital readmissions were found. 12 e-MedRec tools aimed at health professionals have been developed to date but none was designed as a mobile app. The main features that healthcare professionals requested to be included in e-MedRec tools were interoperability, "user-friendly" information, and integration with the ordering process.

PMID:38055124 | DOI:10.1007/s10916-023-02008-0

Int J Drug Policy. 2023 Dec 4;123:104258. doi: 10.1016/j.drugpo.2023.104258. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug use and trading are typically social activities; however, supply through cryptomarkets can occur without any in-person social contact. People who use drugs alone may be at higher risk of experiencing harms, for example, due to lack of others who may call for emergency assistance. Alternatively, cryptomarkets may be a source of harm reduction information and drugs with better-known content and dose, potentially reducing the risk of adverse events. This study examines relationships between cryptomarket use, drug-using social networks and adverse drug events for MDMA, cocaine and LSD.

METHOD: A subsample of 23,053 respondents from over 70 countries was collected in the 2018 Global Drug Survey. People who reported using MDMA, cocaine or LSD were asked about using cryptomarkets to purchase these drugs; any adverse drug events requiring medical treatment (combining seeking treatment and should have sought treatment but did not); and social networks who they had used the specific drug with. All measures referred to the last 12 months, hereon referred to as 'recent'. Binary logistic regressions examined relationships between cryptomarket use, drug-using social networks, and adverse drug events, controlling for age, gender, and frequency of drug use.

RESULTS: Adverse events from any drug type were low (5.2%) and for each drug; MDMA (3.5%); cocaine (3.3%); and LSD (3.5%). After controlling for covariates, recent cryptomarket use was associated with increased likelihood of having no drug-using network for each drug type. People who recently used cryptomarkets were more likely to report adverse cocaine (AOR = 1.70 (1.22-2.37)) and LSD (AOR = 1.58 (1.12-2.09)) events. For those reporting a network size >1, network characteristics did not differ with recent cryptomarket use; however, those reporting recent cryptomarket use were more likely to report adverse LSD events (AOR = 1.86 (0.99-3.51)).

CONCLUSION: People who reported purchasing drugs from cryptomarkets more commonly reported having no drug-using network, and cryptomarket purchase was associated with reported adverse events. Our results support the notion that cryptomarket use increases drug-related harm, but further disentanglement of multiple complex mechanisms is needed in future research.

PMID:38056221 | DOI:10.1016/j.drugpo.2023.104258

Cureus. 2023 Nov 4;15(11):e48272. doi: 10.7759/cureus.48272. eCollection 2023 Nov.

ABSTRACT

Background Caudal epidural anesthesia technique is a relevant method for postoperative analgesia in newborns, allowing for the reduction of drug-induced respiratory depression. The threading of a catheter is, however, uncommon in clinical practice. Our main purpose was to describe our experience regarding caudally inserted epidural catheters in neonates undergoing major abdominal surgery. Methods We included every full-term neonate undergoing surgery under combined caudal epidural-general anesthesia from 2017 to 2022 in our institution. After induction of general anesthesia, an ultrasound-guided caudal epidural injection was performed, and an epidural catheter was inserted for perioperative analgesia. An epidural bolus of ropivacaine was administered to every patient before the surgical incision, and an epidural infusion of ropivacaine 0.05% was administered for 24 hours. Results Retrospectively obtained data included six full-term neonates with American Society of Anesthesiologists (ASA) physical status II to IV. Intraoperatively, good analgesia was achieved without hemodynamic instability or need for additional systemic opioids after induction. At the end of surgery, five of the six neonates were extubated without adverse respiratory events. Postoperatively, effective analgesia was achieved in four cases with an epidural infusion of ropivacaine 0.05%, at a rate between 0.2 and 0.4 mg/kg/h, and intravenous paracetamol. Epidural pain control was not successful in one neonate, and thus an intravenous fentanyl infusion was added. The sixth neonate remained intubated for prolonged mechanical ventilation due to surgical complications, and thus an intravenous fentanyl infusion was introduced for sedation in the neonatal intensive care unit (NICU), not allowing to evaluate the effectiveness of the epidural infusion alone. No other complications related to the epidural catheters were reported. Conclusion Continuous caudal epidural analgesia may be a valuable technique with a low risk of complications, decreasing the incidence of respiratory adverse events in this patient population. Although more cases are needed for a stronger conclusion, it has become a useful analgesic strategy for major abdominal surgery in neonates in our institution.

PMID:38054162 | PMC:PMC10695668 | DOI:10.7759/cureus.48272

J Drugs Dermatol. 2023 Dec 1;22(12):e42-e43. doi: 10.36849/JDD.6532.

ABSTRACT

Actemra (tocilizumab) received emergency use authorization for the treatment of coronavirus disease 2019 (COVID-19) in June 2021. Literature has linked numerous cutaneous adverse effects to tocilizumab. In this current survey, investigators reviewed and compared these adverse effects to the common cutaneous manifestations of COVID-19. While similarities in patient presentation exist, important distinctions are made to aid dermatologists in their clinical diagnosis. &nbsp;J Drugs Dermatol. 2023;22(12):e42-e43.&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.6532e.

PMID:38051828 | DOI:10.36849/JDD.6532

Clin Infect Dis. 2023 Dec 5;77(Supplement_6):S487-S496. doi: 10.1093/cid/ciad642.

ABSTRACT

Live biotherapeutic products (LBPs) represent a new class of therapeutics indicated to prevent the recurrence of Clostridioides difficile infection (CDI) in adults. However, microbiota-based therapies have been used in CDI management before the Food and Drug Administration (FDA) designated this new drug class. The regulation of these microbiome-based therapies has varied, and several safety concerns have arisen over time. Requirements established by the FDA regarding the development of LBPs minimizes many of these prior concerns, and phase III trials have proven the safety and efficacy of 2 stool donor-derived LBPs: fecal microbiota, live-jslm (Rebyota™; formerly RBX2660) and fecal microbiota spores, live-brpk (Vowst™; formerly SER-109). Mild gastrointestinal side effects are common, but no severe drug-related adverse events have been reported with their use to date. A third LBP entering phase III clinical trials, VE303, follows a novel approach by sourcing bacterial strains from clonal cell banks and has demonstrated a similarly favorable safety profile.

PMID:38051970 | DOI:10.1093/cid/ciad642

Clin Ophthalmol. 2023 Nov 29;17:3645-3653. doi: 10.2147/OPTH.S439255. eCollection 2023.

ABSTRACT

PURPOSE: Clinically, glaucoma is a serious problem because it is asymptomatic until a relatively late stage in most cases, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of glaucoma with the causative drugs using a spontaneous reporting system database.

METHODS: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on reports of glaucoma caused by all drugs, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for glaucoma.

RESULTS: Among 609 reports of adverse events corresponding to glaucoma (46%, women), the most frequently implicated drug were steroids (prednisolone, betamethasone sodium phosphate, triamcinolone acetonide, and fluorometholone), pregabalin, ranibizumab, crizotinib, tacrolimus hydrate, darbepoetin alfa, and foscarnet sodium hydrate. Among 207 reports involved in angle-closure glaucoma (86%, women), anticholinergic drug and antidepressants ranked high and showed signals. Signals were also detected in bromazepam (ROR, 69.7; 95% CI, 30.9-157.5), oral brotizolam (ROR, 16.6; 95% CI, 6.18-44.8), and oral milnacipran hydrochloride (ROR, 22.8; 95% CI, 8.46-61.4) for angle-closure glaucoma.

CONCLUSION: A national pharmacovigilance database enabled us to identify the drugs that frequently induce glaucoma. The likelihood of the reporting of glaucoma varied among the drugs, which should be used carefully in clinical practice to avoid it.

PMID:38050555 | PMC:PMC10693769 | DOI:10.2147/OPTH.S439255

Pharmacotherapy. 2023 Dec 4. doi: 10.1002/phar.2898. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Failure of initial benzodiazepine therapy in patients with status epilepticus warrants urgent administration of a second-line antiseizure medication. Recent studies suggest rapid administration of high-dose, undiluted levetiracetam is safe in adults; however, no information exists in pediatric patients. The purpose of this study was to evaluate the safety and tolerability of undiluted levetiracetam at a pediatric institution.

METHODS: Retrospective, single-center, cohort analysis of patients who received high-dose >60 mg/kg (-10%) up to 4500 mg diluted or undiluted intravenous levetiracetam between May 6, 2020 to July 31, 2022 at a large pediatric academic medical center. The primary outcome was the assessment of hemodynamic disturbances (bradycardia, hypotension) and/or infusion-related reactions after administration of the levetiracetam infusion.

RESULTS: A total of 776 levetiracetam doses were included, 358 doses administered and 418 doses wasted. The doses administered (61 undiluted and 297 diluted) accounted for a total of 252 patients (39 received undiluted and 213 received diluted levetiracetam) (median [minimum-maximum range] age, 2 y [1 d-32.7 y]; mean (standard deviation [SD]) weight, 20.1 kg (22.1 kg)). The incidence of hemodynamic disturbances and infusion-related reactions was not statistically significant between diluted and undiluted groups (p= 0.87). The median (interquartile range [IQR]) time difference between first-line antiseizure medication and levetiracetam administration in patients with status epilepticus was 18 minutes (10.5-30.5) in the undiluted group versus 36.5 minutes (21.8-67.3) in the diluted group; p<0.01. Additionally, there was a significant amount of drug waste from dispensed but not administered doses of the diluted bag compared to undiluted vials (57.6% diluted versus 18.7% undiluted, p<0.001).

CONCLUSION: Undiluted levetiracetam was not associated with an increased incidence of adverse effects compared to diluted levetiracetam in high-doses, up to 4500 mg given over 5 minutes in pediatric patients.

PMID:38050327 | DOI:10.1002/phar.2898

Reg Anesth Pain Med. 2023 Nov 30:rapm-2023-104941. doi: 10.1136/rapm-2023-104941. Online ahead of print.

ABSTRACT

BACKGROUND/IMPORTANCE: Arachnoiditis is a rare but devastating disorder caused by various insults, one of which is purported to be local anesthetic neurotoxicity following neuraxial blockade. However, the relationship between local anesthetics administered into the neuraxis and the development of arachnoiditis has not been clearly elucidated.

OBJECTIVE: We aimed to summarize the existing complex body of literature and characterize both the essential features and strength of any association between neuraxial local anesthetic neurotoxicity and arachnoiditis with a view toward mitigating risk, enhancing prevention, and refining informed consent discussions.

EVIDENCE REVIEW: We reviewed all published reports of arachnoiditis attributed to local anesthetic neurotoxicity following perioperative neuraxial anesthesia. This narrative review was based on a systematic search methodology, which included articles published up until December 2022.

FINDINGS: Thirty-eight articles were included, comprising 130 patients, over one-half of which were published prior to this century and inconsistent with modern practice. Neuraxial techniques included 78 epidurals, 48 spinals, and 5 combined spinal-epidurals, mostly for obstetrics. Reporting of essential procedural data was generally incomplete. Overall, at least 57% of patients experienced complicated needle/catheter insertion, including paresthesia, pain, or multiple attempts, irrespective of technique. The onset of neurological symptoms ranged from immediate to 8 years after neuraxial blockade, while the pathophysiology of arachnoiditis, if described, was heterogeneous.

CONCLUSIONS: The existing literature attributing arachnoiditis to local anesthetic neurotoxicity is largely outdated, incomplete, and/or confounded by other potential causes, and thus insufficient to characterize the features and strength of any association.

PMID:38050164 | DOI:10.1136/rapm-2023-104941

Drug Ther Bull. 2023 Dec 2:dtb-2023-000063. doi: 10.1136/dtb.2023.000063. Online ahead of print.

NO ABSTRACT

PMID:38050092 | DOI:10.1136/dtb.2023.000063

Drug Ther Bull. 2023 Nov 24:dtb-2023-000064. doi: 10.1136/dtb.2023.000064. Online ahead of print.

NO ABSTRACT

PMID:38050011 | DOI:10.1136/dtb.2023.000064

Sci Rep. 2023 Dec 4;13(1):21365. doi: 10.1038/s41598-023-46909-z.

ABSTRACT

As demand for renewable energy is rising, wind power development is rapidly growing worldwide. In its wake, conflicts arise over land use changes converting pristine nature into industrial power plants and its associated adverse biodiversity effects, crowned by one of the most obvious and deadly consequences: bird collisions. Most post-construction studies report low levels of avian mortality, but the majority of these studies are conducted primarily on larger birds. However, the diversity and abundance of small passerine birds are rarely reflected in the carcass surveys, although they in numeric proportion to their abundances should be the most numerous. The assumption that surveys find all carcasses seems thus rarely fulfilled and passerine mortality is likely to be grossly underestimated. We therefore designed an experiment with dummy birds to estimate mortality of small-bodied passerines and other small-bodied birds during post-construction surveys, tested in a medium-sized wind farm in western Norway. The wind farm was surveyed weekly during the migration periods by carcass survey teams using trained dogs to find killed birds. The dogs in the carcass surveys were more successful in locating the large than the small dummy birds (60-200 g), where they found 74% of the large dummy birds. Detecting the smaller category (5-24 g) was more demanding and the dogs only found 17% of the small dummy birds. Correcting the post-construction carcass survey outcome with the results from the experiment leads to an almost fourfold increase in estimated mortality rates, largely due to the low detection rate of the smallest category. The detection rates will naturally vary between wind farms, depending on the specific habitat characteristics, the efficiency of the carcass surveys and the search intervals. Thus, implementing a simple experiment with dummy birds to future post-construction surveys will produce more accurate estimates of the wind turbine mortality rates, and thus improve our understanding of the biodiversity effects of conforming to a more sustainable future.

PMID:38049460 | PMC:PMC10695956 | DOI:10.1038/s41598-023-46909-z

Pharmacotherapy. 2023 Dec 4. doi: 10.1002/phar.2897. Online ahead of print.

ABSTRACT

Concomitant pain syndromes and cardiovascular disease (CVD) and disorders are associated with significant morbidity, impaired quality of life, and neuropsychiatric disorders. There is an interplay between the mechanisms of pathophysiology of both CVD and pain syndromes. Patients with CVD (and/or disorders) as well as pain syndromes have an increased propensity for drug-drug/disease interactions. Therefore, an understanding of how to use pharmacotherapy to treat pain syndromes, in the context of patients who have diagnoses of CVD and/or disorders, is paramount to patients' success in achieving adequate pain control and appropriately managing CVD and/or disorders, all while decreasing the risk of adverse events (AEs) both from pharmacotherapy to treat pain and CVD (and/or disorders). Based on the appraisal of literature and authors' clinical expertise, it was determined that gabapentinoids, opioids, skeletal muscle relaxants, tricyclic antidepressants, clonidine, serotonin norepinephrine-reuptake inhibitors, dronabinol, carbamazepine, second generation antipsychotics, non-steroidal anti-inflammatory drugs, aspirin, corticosteroids, and topical anesthetics have the most evidence with use in patients with CVD and/or disorders. However, the literature surrounding the use of pharmacotherapy for pain management are limited to retrospective studies and there is a lack of well-designed, prospective, randomized trials; this also included head-to-head comparator studies. Unlike many CVD-related pharmacotherapy studies, data studying pain management in patients with CVD lacks standardized outcomes that are consistent among the pool of data. Overall, the decision of prescribing specific pain management therapies in patients with CVD and/or disorders should include assessment of pain severity, type of pain, drug-drug/disease interactions, adjuvant therapies required, and the risk or presence of AEs.

PMID:38049207 | DOI:10.1002/phar.2897

Epilepsia Open. 2023 Dec 4. doi: 10.1002/epi4.12875. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs).

METHODS: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 seconds) confirmed by video-electroencephalography, and inadequate seizure control with ≥1 ASMs. A screening period (up to 36 hours) was followed by a 48-hour evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs).

RESULTS: Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All 6 patients completed the evaluation period; 2 entered and completed the extension period. Overall (evaluation and extension periods), 3 patients received 1 dose of 0.5 mg/kg BRV and 3 received >1 dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n=6). At 0.5-1, 2-4, and 8-12 hours following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n=5]), 0.50 mg/L (28.20% [n=6]) and 0.34 mg/L (13.20% [n=5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced 4 TEAEs, none of which were considered related to BRV.

SIGNIFICANCE: BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg twice daily. BRV was well-tolerated, with no drug-related TEAEs reported.

PMID:38049197 | DOI:10.1002/epi4.12875

Front Immunol. 2023 Nov 17;14:1275368. doi: 10.3389/fimmu.2023.1275368. eCollection 2023.

ABSTRACT

INTRODUCTION: Hepatotoxicity induced by immunotherapeutics is an appearing cause for immune-mediated drug-induced liver injury. Such immuno-toxic mechanisms are difficult to assess using current preclinical models and the incidence is too low to detect in clinical trials. As hepatotoxicity is a frequent reason for post-authorisation drug withdrawal, there is an urgent need for immuno-inflammatory in vitro models to assess the hepatotoxic potential of immuno-modulatory drug candidates. We developed several immuno-inflammatory hepatotoxicity test systems based on recombinant human interleukin-2 (aldesleukin).

METHODS: Co-culture models of primary human CD8+ T cells or NK cells with the hepatocyte cell line HepaRG were established and validated with primary human hepatocytes (PHHs). Subsequently, the HepaRG model was refined by increasing complexity by inclusion of monocyte-derived macrophages (MdMs). The main readouts were cytotoxicity, inflammatory mediator release, surface marker expression and specific hepatocyte functions.

RESULTS: We identified CD8+ T cells as possible mediators of aldesleukin-mediated hepatotoxicity, with MdMs being implicated in increased aldesleukin-induced inflammatory effects. In co-cultures of CD8+ T cells with MdMs and HepaRG cells, cytotoxicity was induced at intermediate/high aldesleukin concentrations and perforin was upregulated. A pro-inflammatory milieu was created measured by interleukin-6 (IL-6), c-reactive protein (CRP), interferon gamma (IFN-γ), and monocyte chemoattractant protein-1 (MCP-1) increase. NK cells responded to aldesleukin, however, only minor aldesleukin-induced cytotoxic effects were measured in co-cultures. Results obtained with HepaRG cells and with PHHs were comparable, especially regarding cytotoxicity, but high inter-donor variations limited meaningfulness of the PHH model.

DISCUSSION: The in vitro test systems developed contribute to the understanding of potential key mechanisms in aldesleukin-mediated hepatotoxicity. In addition, they may aid assessment of immune-mediated hepatotoxicity during the development of novel immunotherapeutics.

PMID:38045689 | PMC:PMC10693457 | DOI:10.3389/fimmu.2023.1275368

J Arrhythm. 2023 Oct 3;39(6):928-936. doi: 10.1002/joa3.12936. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database.

METHODS: From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP.

RESULTS: Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3).

CONCLUSIONS: This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

PMID:38045460 | PMC:PMC10692844 | DOI:10.1002/joa3.12936

Front Pharmacol. 2023 Nov 17;14:1204075. doi: 10.3389/fphar.2023.1204075. eCollection 2023.

ABSTRACT

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

PMID:38044946 | PMC:PMC10691362 | DOI:10.3389/fphar.2023.1204075