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Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1−/− mice are more susceptible to drug-induced liver injury, but PD-1−/− mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1−/− mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one‐sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical "hapten" hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p‐i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross‐reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross‐reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs. [ABSTRACT FROM AUTHOR]

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI. [ABSTRACT FROM AUTHOR]

We present a case of a young male from a low socioeconomic background who presented with mucosal ulceration, hematemesis episodes, and pancytopenia following treatment with trimethoprim-sulfamethoxazole (TMP-SMX) for a urinary tract infection. On examination, the patient exhibited signs of severe anemia and hemodynamic instability. After stabilization and a thorough workup a diagnosis of idiosyncratic drug reaction secondary to TMP-SMX was established, believed to be exacerbated by the patient's immune-hyperactive state due to a recent HIV diagnosis. Initiation of methylprednisolone therapy resulted in rapid improvement in blood parameters. This case highlights the complexity of TMP-SMX-induced pancytopenia in the context of HIV infection and emphasizes the prompt recognition and management of such life-threatening adverse reactions in immunocompromised individuals. [ABSTRACT FROM AUTHOR]

COVID-19 vaccination has been associated with myocarditis in adolescents and young adults, and concerns have been raised about possible vaccine-related cardiac fatalities in this age group. In April 2021, cases of myocarditis after COVID-19 vaccination, particularly among young male vaccine recipients, were reported to the Vaccine Adverse Event Reporting System. To assess this possibility, investigators searched death certificates for Oregon residents aged 16-30 years who died during June 2021-December 2022 for cardiac or undetermined causes of death. For identified decedents, records in Oregon's immunization information system were reviewed for documentation of mRNA COVID-19 vaccination received =100 days before death. Among 1,292 identified deaths, COVID-19 was cited as the cause for 30. For 101 others, a cardiac cause of death could not be excluded; among these decedents, immunization information system records were available for 88, three of whom had received an mRNA COVID-19 vaccination within 100 days of death. Of 40 deaths that occurred among persons who had received an mRNA COVID-19 vaccine dose, three occurred =100 days after vaccination. Two of these deaths were attributed to chronic underlying conditions; the cause was undetermined for one. No death certificate attributed death to vaccination. These data do not support an association between receipt of mRNA COVID-19 vaccine and sudden cardiac death among previously healthy young persons. COVID-19 vaccination is recommended for all persons aged =6 months to prevent COVID-19 and complications, including death. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine. [ABSTRACT FROM AUTHOR]

This Note advocates for congressional and state action to remedy the Supreme Court's flawed 2022 decision in Ruan v. United States. This approach includes a modified return to the objective good faith defense established by the Controlled Substances Act of 1970 (CSA) and United States v. Moore, the 1975 seminal case that established that physicians could be prosecuted under 21 U.S.C. § 841. Ruan requires that the government show a defendant physician subjectively knew their conduct in issuing controlled substances was unlawful. This permits the substitution of an individual physician's conception of acceptable medical practice in place of a generally agreed upon standard when a jury decides whether the physician prescribed in good faith. The Ruan decision is inconsistent with the text and intent of the CSA and the objective good faith defense standard established in Moore. Further, it is incongruous with the Supreme Court's 2006 decision in Gonzales v. Oregon, which delegated authority to the states, not individual physicians, to determine the bounds of acceptable medical practice. Additionally, Ruan had the unintended consequence of exacerbating a treatment disparity between low-level drug couriers and physicians charged under the CSA. This Note argues that a comprehensive, uniform amendment to the CSA, state prescribing statutes, and federal agency prescribing guidelines clearly defining what constitutes lawful prescribing would fulfill the Ruan Court's aims and maintain consistency with the CSA and the Supreme Court's prior holdings. Simultaneously, it would prevent the inequity between drug couriers and physicians from intensifying. [ABSTRACT FROM AUTHOR]

Delayed drug hypersensitivity reactions (DDHRs) represent a major health problem. They are unpredictable and can cause life-long disability or even death. The pathophysiology of DDHRs is complicated, multifactorial, and not well understood mainly due to the lack of validated animal models or in vitro systems. The role of the immune system is well demonstrated but its exact pathophysiology still a matter of debate. This review summarizes the current understanding of DDHRs pathophysiology and abridges the available new evidence supporting each hypothesis. A comprehensive literature search for relevant publications was performed using PubMed, Google Scholar, and Medline databases with no date restrictions and focusing on the most recent 10 years. Although multiple milestones have been achieved in our understanding of DDHRs pathophysiology as a result of the development of useful experimental models, many questions are yet to be fully answered. A deeper understanding of the mechanistic basis of DDHRs would not only facilitate the development of robust and reliable diagnostic assays for diagnosis, but would also inform therapy by providing specific target(s) for immunomodulation and potentially permit pre-therapeutic risk assessment to pursue the common goal of safe and effective drug therapy. [ABSTRACT FROM AUTHOR]

Copyright of Ruch Prawniczy, Ekonomiczny i Socjologiczny (0035-9629) is the property of Adam Mickiewicz University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The anticonvulsant valproic acid (VA) is associated with a range of idiosyncratic drug reactions; the most common is liver injury. The liver injury can take several forms: hyperammonemia with encephalopathy, liver injury with hepatic microvesicular steatosis, liver injury without steatosis, and a Reye's-like syndrome. The most common form leading to liver failure is the injury with hepatic microvesicular steatosis. This is different from most drug-induced idiosyncratic liver injury. Children under the age of 2 and those with inborn errors in metabolism are at increased risk. VA is a simple branched carboxylic acid, but it is metabolized to >20 metabolites. One metabolite, 2-n-propyl-4-pentenoic acid, resembles the structure of hypoglycin A, the cause of Jamaican Vomiting Sickness. However, there does not appear to be a good correlation between the level of this metabolite and liver injury. Tom Baillie discovered that the 4-ene metabolite is further metabolized to the reactive 2,4-diene. There appears to be a correlation between the amount of the N-acetylcysteine conjugate of the 2,4-diene in the urine of patients and the risk of liver injury. There are many hypotheses as to how VA and its metabolites cause liver injury. It obviously causes mitochondrial injury, which is the basis for the microvesicular steatosis and hyperammonemia. It decreases the levels of Co-enzyme A and carnitine, but that is not sufficient to explain the liver injury. It also causes oxidative stress and changes in DNA methylation, but it is not clear what is responsible for the idiosyncratic nature of valproate-induced liver failure. [ABSTRACT FROM AUTHOR]

Clinical supervisors are known to assess trainee performance idiosyncratically, causing concern about the validity of their ratings. The literature on this issue relies heavily on retrospective collection of decisions, resulting in the risk of inaccurate information regarding what actually drives raters' perceptions. Capturing in-the-moment information about supervisors' impressions could yield better insight into how to intervene. The purpose of this study, therefore, was to gather "real-time" judgments to explore what drives preceptors' judgments of student performance. We performed a prospective study in which physicians were asked to adjust a rating scale in real-time while watching two video-recordings of trainee clinical performances. Scores were captured in 1-s increments, examined for frequency, direction, and magnitude of adjustments, and compared to assessors' final entrustability judgment as measured by the modified Ottawa Clinic Assessment Tool. The standard deviation in raters' judgment was examined as a function of time to determine how long it takes impressions to begin to vary. 20 participants viewed 2 clinical vignettes. Considerable variability in ratings was observed with different behaviours triggering scale adjustments for different raters. That idiosyncrasy occurred very quickly, with the standard deviation in raters' judgments rapidly increasing within 30 s of case onset. Particular moments appeared to generally be influential, but their degree of influence still varied. Correlations between the final assessment and (a) score assigned upon first adjustment of the scale, (b) upon last adjustment, and (c) the mean score, were r = 0.13, 0.32, and 0.57 for one video and r = 0.30, 0.50, and 0.52 for the other, indicating the degree to which overall impressions reflected accumulation of raters' idiosyncratic moment-by-moment observations. Our results demonstrated that variability in raters' impressions begins very early in a case presentation and is associated with different behaviours having different influence on different raters. More generally, this study outlines a novel methodology that offers a new path for gaining insight into factors influencing assessor judgments. [ABSTRACT FROM AUTHOR]

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC–MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert. [ABSTRACT FROM AUTHOR]

Background: Evidence supports an important link between mitochondrial DNA (mtDNA) variation and adverse drug reactions such as idiosyncratic drug-induced liver injury (iDILI). Here, we describe the generation of HepG2-derived transmitochondrial cybrids, to investigate the impact of mtDNA variation on mitochondrial (dys)function and susceptibility to iDILI. This study created 10 cybrid cell lines, each containing distinct mitochondrial genotypes of haplogroup H or haplogroup J backgrounds. Methods: HepG2 cells were depleted of mtDNA to make rho zero cells, before the introduction of known mitochondrial genotypes using platelets from healthy volunteers (n=10), thus generating 10 transmitochondrial cybrid cell lines. The mitochondrial function of each was assessed at basal state and following treatment with compounds associated with iDILI; flutamide, 2-hydroxyflutamide, and tolcapone, and their less toxic counterparts bicalutamide and entacapone utilizing ATP assays and extracellular flux analysis. Results: Whilst only slight variations in basal mitochondrial function were observed between haplogroups H and J, haplogroup-specific responses were observed to the mitotoxic drugs. Haplogroup J showed increased susceptibility to inhibition by flutamide, 2-hydroxyflutamide, and tolcapone, via effects on selected mitochondrial complexes (I and II), and an uncoupling of the respiratory chain. Conclusions: This study demonstrates that HepG2 transmitochondrial cybrids can be created to contain the mitochondrial genotype of any individual of interest. This provides a practical and reproducible system to investigate the cellular consequences of variation in the mitochondrial genome, against a constant nuclear background. Additionally, the results show that inter-individual variation in mitochondrial haplogroup may be a factor in determining sensitivity to mitochondrial toxicants. [ABSTRACT FROM AUTHOR]

Offense lurks behind the political cartoon like its shadow, capable of creating mixed reactions in the target. In terms of offense-giving, cartoonists are sometimes cautious and at other times cavalier, thereby causing intentional and inadvertent offense, respectively. This article examines the aspects of the political cartoon that facilitate the performance of offense, which is predominantly visual in nature. The article takes the position that there must be an earnest attempt at delimiting offense-giving. In order to emphasize this ethical turn, the authors attempt a delimitation exercise by experimenting with a select controversial cartoon. [ABSTRACT FROM AUTHOR]

There has been widespread implementation of pharmacogenomic testing to inform drug prescribing in medical specialties such as oncology and cardiology. Progress in using pharmacogenomic tests when prescribing antimicrobials has been more limited, though a relatively large number of pharmacogenomic studies on aspects such as idiosyncratic adverse drug reactions have now been performed for this drug class. Currently, there are recommendations in place from either National Regulatory Agencies and/or specialist Pharmacogenomics Advisory Groups concerning genotyping for specific variants in MT-RNR1 and CYP2C19 before prescribing aminoglycosides and voriconazole, respectively. Numerous additional pharmacogenomic associations have been reported concerning antimicrobial-related idiosyncratic adverse drug reactions, particularly involving specific HLA alleles, but, to date, the cost-effectiveness of genotyping prior to prescription has not been confirmed. Polygenic risk score determination has been investigated to a more limited extent but currently suffers from important limitations. Despite limited progress to date, the future widespread adoption of preemptive genotyping and genome sequencing may provide pharmacogenomic data to prescribers that can be used to inform prescribing and increase the safe use of antimicrobials. [ABSTRACT FROM AUTHOR]

Immune‐mediated type IV adverse drug reactions are idiosyncratic in nature, generally not related to the primary or secondary pharmacology of the drug. Due to their complex nature and rarity, these iatrogenic reactions are seldom predicted or encountered during preclinical/early clinical development stages, and often precipitate upon exposure to wider populations (i.e. phase III onwards). They confer a burden on the healthcare sector in both a clinical and financial sense presenting a severe impediment to the drug discovery and development process. Research over the past 50 years has improved our understanding of these reactions markedly as both in vitro and in vivo studies have placed the role of the immune system, in particular; drug‐responsive T cells, firmly in the spotlight as the mediators of these reactions. Indeed, the role of different populations of T cells in adverse events and the interaction of drug molecules with HLA proteins expressed on the surface of antigen‐presenting cells is of considerable interest. Herein, this review examines the pathways of immune‐mediated adverse events including the various T cell subtypes implicated and the mechanisms of T cell activation. Additionally, we address the enigma of immunological tolerance and explore the role tolerance plays in determination of susceptibility to such adverse events even in individuals carrying immunogenic liabilities. [ABSTRACT FROM AUTHOR]

Objective: To describe 4 canine cases of presumed zonisamide-induced blood dyscrasias. Case summary: From 2007 to 2018 at Angell Animal Medical Center and from 2014 to 2019 at the Cummings School of Veterinary Medicine at Tufts University, 4 dogs presented with febrile neutropenia while being administered zonisamide. No septic focus was found on workup for any of the dogs, and the clinical signs were attributed to an idiosyncratic drug reaction. AllWBC counts returned to normal with drug withdrawal, and all dogs survived. New or unique information provided: Presumptive zonisamide-induced blood dyscrasias are a rare complication that has not previously been reported in the veterinary literature. [ABSTRACT FROM AUTHOR]

Copyright of Realidad Economica is the property of Realidad Economica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Drug hypersensitivity reactions are immunologically mediated reactions resulting in the production of drug-specific antibodies and/or T-cells and constituting only <15% of all drug reactions. Based on the clinical observations, both patients and their parents refer to any undesirable drug reactions as drug allergy, regardless of whether the underlying mechanism is immunological or not. After allergy examinations, only a small percentage of the patients who were reported positive for drug reactions based on their clinical history are actually confirmed to have hypersensitivity. This study aims to determine the actual frequency of drug allergies in children, the drugs that cause the most common allergies in patients with a complaint of drug allergy and evaluate the accompanying demographic and clinical features. Methods: The study evaluated data from a total of 266 patients (ages of 0-18) with suspected drug allergy during a 3-year period. Twenty-four patients with doctor-diagnosed drug-related anaphylaxis and 85 patients who did not accept diagnostic tests were excluded from the study and the study continued with a total of 157 patients. The allergy work-up consisted of in vivo and in vitro tests, in accordance with the recommendations of the ENDA/EAACI guidelines. Results: Data from a group of 157 patients (M [54.6%]; F [45.4%]) were retrospectively analyzed. Beta-lactams (BLs) were the most common drugs involved in the reported clinical history followed by non-steroidal antiinflammatory drugs (NSAIDs). Allergic reactions occurred on the median 1st day (min: 1-max: 8) after drug intake and were most frequently observed as urticaria (55.3%). Immediate reactions (IRs) were observed in 53.5% and non-IRs in 46.5% of the patients. Conclusion: Our data demonstrated that only 15.5% of patients confirmed to be positive to allergy during testing which is in line with the data in the literature. An allergy work-up is mandatory for excluding suspected hypersensitivity. [ABSTRACT FROM AUTHOR]

Aim: Drug hypersensitivity is an important issue encountered by clinicians during clinical practice in Turkey and in the world. Any drug used for diagnosis or treatment has the potential to cause hypersensitivity reactions. The aim of the present study was to review the distribution of drugs reported to cause hypersensitivity reactions and to determine the distribution of tests and test results among patients that presented to the adult allergy and immunology outpatient clinic with immediate-type drug hypersensitivity in the Malatya province. Materials and Methods: The study included adult patients who were admitted with immediate-type drug hypersensitivity (allergic and/or non-allergic) between October 2017 and October 2020 and underwent testing for drugs. Age, sex, atopic diseases (asthma, allergic rhinitis, urticaria, eczema), culprit drug(s), drug reaction types, time of reaction onset, and skin and drug provocation test results were evaluated. Results: Of the 107 patients included, 83 (77.6%) were female and 24 (22.4%) were male. The mean age was 40.74 ± 11.28 years. There was a history of drug hypersensitivity to antibiotics in 44 patients (41.1%) and analgesics in 56 patients (52.3%). Urticaria and/or angioedema were the most common reactions to culprit drugs. Overall, 148 tests for drug hypersensitivity were performed, and the positivity rate was 6.1%. Conclusion: Analgesics and antibiotics were the most common causative agents in patients presenting to allergy outpatient clinics with drug allergy, and reactions occurred even with alternative agents. Thus, patients reporting drug reactions should undergo drug tests before physicians recommend drugs. [ABSTRACT FROM AUTHOR]

This paper draws upon recent research into leadership and the use of power in the virtual space and also upon the author's nineteen years as a facilitator of Virtual Action Learning (VAL) and Virtual Leadership (VL) training. This paper briefly surveys various developments in the last twenty years which have nudged us as people and organisations into more virtual ways of working and learning. The author's belief is that VAL, and virtual collaboration generally, constitute a different paradigm of interaction with its own idiosyncrasies and is therefore different in many ways from what we have learned from face-to-face experience. This account of practice combines some key findings from the author's latest research with the learning from her practice over these years. Five main lessons emerge for facilitators of VAL and virtual leadership including the effects of using cameras and different channels of communication on power dynamics and the importance of voice and silence in the virtual space. [ABSTRACT FROM AUTHOR]

Many drugs can bind directly to proteins or be bioactivated by metabolizing enzymes to form reactive metabolites (RMs) that rapidly bind to proteins to form drug−protein conjugates or metabolite−protein conjugates (DMPCs). The close relationship between DMPCs and idiosyncratic adverse drug reactions (IADRs) has been recognized; drug discovery teams tend to avoid covalent interactions in drug discovery projects. Covalent interactions in DMPCs can provide high potency and long action duration and conquer the intractable targets, inspiring drug design, and development. This forms the dual role feature of DMPCs. Understanding the functional implications of DMPCs in IADR control and therapeutic applications requires precise identification of these conjugates from complex biological samples. While classical biochemical methods have contributed significantly to DMPC detection in the past decades, the low abundance and low coverage of DMPCs have become a bottleneck in this field. An emerging transformation toward shotgun proteomics is on the rise. The evolving shotgun proteomics techniques offer improved reproducibility, throughput, specificity, operability, and standardization. Here, we review recent progress in the systematic discovery of DMPCs using shotgun proteomics. Furthermore, the applications of shotgun proteomics supporting drug development, toxicity mechanism investigation, and drug repurposing processes are also reviewed and prospected. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic drug reaction hallmarked by cutaneous eruption, fever, lymphadenopathy, multiorgan involvement, and hematological abnormalities, most often eosinophilia and atypical lymphocytosis. Leukemoid reactions have rarely been described in DRESS syndrome and here we describe a 16‐year‐old male who was admitted to the hospital with DRESS syndrome due to minocycline, who had a severe leukocytosis up to 52.08 K/μL. He improved with cessation of minocycline and initiation of systemic steroids. We report this case to add to the literature on hematological abnormalities in pediatric DRESS syndrome. [ABSTRACT FROM AUTHOR]

Background: Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare idiosyncratic and unpredictable drug reaction most commonly attributed to anticonvulsants, allopurinol, and antibiotics. Fever in combination with cutaneous manifestations and eosinophilia are the cardinal clinical findings, while organ involvement and very rarely pancytopenia can be present. Case presentation: We describe a 26-year-old female patient with pancytopenia in the context of lamotrigine-induced DRESS and we summarize this as a potentially life-threatening hypersensitivity reaction. Conclusion: DRESS should be suspected in patients presenting with fever, eosinophilia, skin involvement, and/or visceral organ involvement, who have started a new drug during the past 2 to 6 weeks, as early recognition of this syndrome with subsequent discontinuation of the offending drug could be lifesaving. [ABSTRACT FROM AUTHOR]

Cerebellar ataxic syndromes, although uncommon, have been reported previously in patients taking metronidazole. However, almost all cases describe instances where patients were taking prolonged or high doses of the drug. We report a 65-year-old man who consumed 400 mg of metronidazole 3 times over 1 day and presented with slurring of speech, imbalance while walking and diplopia. The symptoms developed the day after consumption of metronidazole. Examination showed slurring of speech, gaze-evoked nystagmus, and dysmetria in all limbs. MRI brain revealed symmetric hyperintense lesions in the dentate nucleus and pons on T2-weighted imaging and FLAIR, which have a well-established association with metronidazole-induced central nervous system (CNS) toxicity. On discontinuation of the drug, symptoms improved, and complete recovery was noted at follow-up 2 weeks later. This case indicates that CNS side effects of metronidazole may not necessarily occur only at high doses or after prolonged courses of metronidazole, but may occur as an idiosyncratic reaction to the drug. Reasons for variable susceptibility require further investigation. [ABSTRACT FROM AUTHOR]

Identifying pharmaceutical technology opportunities can help guide drug innovation effectively and reduce the failure rate of pharmaceutical research and development (R&D) activities. Multiple factors are neatly associated with pharmaceutical R&D activities. Adverse drug reaction (ADR) is one of the main reasons for drug R&D failure. However, the current technology opportunities identification (TOI) approaches seldom try to identify pharmaceutical-specific technology opportunities from the perspective of ADR. Except that, pharmaceutical R&D activities are a complex process involving the interaction of disease, drug, and gene. Nevertheless, pharmaceutical TOI research often overlooks the relationships among various diseases, ADRs, drugs, and genes. In response, this article proposed a domain-specific multilayer network framework for pharmaceutical TOI from the standpoint of ADRs. Compared with previous research, there are three extensions. The first extension is identifying pharmaceutical TOI from the ADR's perspective. The second extension is identifying pharmaceutical technological opportunities based on multilayer networks. The last extension is integrating multi-source data in multilayer networks. Then, the proposed framework is applied to hyperuricemia drugs to prove their efficiency and effectiveness. This framework helps explain the complex relationships among diseases, ADRs, drugs, and genes. Furthermore, the analysis results provide interesting insight into pharmaceutical TOI and extend the multilayer network theory. • Adverse drug reaction is one of the main reasons for pharmaceutical technology R&D failure. • Pharmaceutical technology opportunity identification has innovation dilemmas. • Identifying pharmaceutical technology opportunities from the view of ADRs adopt multilayer networks can mitigate those dilemmas. • This article proposes a systematic and specific framework to develop that multilayer network. • Machine learning and multilayer networks can combine as effective analytical tools. [ABSTRACT FROM AUTHOR]

Although agomelatine may be associated with an increased risk of hepatotoxicity, the incidence rate of acute hepatitis seemed divergent between clinical trials and daily practice. Whether aging or gender is a risk factor in developing hepatotoxicity due to agomelatine is not clear. We present 3 older female cases with acute hepatitis occurring due to highly probable idiosyncratic drug-induced liver injury caused by agomelatine. From these cases, regular surveillance on liver function in the older women taking antidepressants would be of benefits. [ABSTRACT FROM AUTHOR]

Introduction: Treatment is generally not available for drug-induced liver injury (DILI) patients except in some specific circumstances. The management of DILI is based on the withdrawal of the responsible drug and monitoring the patients and only a few patients need to be referred to a transplant center. Some studies on the role of ursodeoxycholic acid (UDCA) in DILI have been published. The aim of this study was to perform a systematic review of the role of UDCA in the treatment and prevention of DILI. Methods: A search was undertaken in PubMed, with the key words ursodeoxycholic acid, drug-induced liver injury and hepatotoxicity following the PRISMA guidelines. Results: A total of 33 publications were identified: 25 case reports and 8 case series. In 18 of the 25 cases reports (22 patients), authors reported improvement of liver injury associated with UDCA therapy whereas 7 case reports did not show clinical or biochemical improvement after UDCA treatment. There were 4 studies evaluating the role of UDCA in the treatment of DILI, three prospective (one being a clinical trial) and one retrospective studies. Three studies observed liver profile improvements associated with UDCA. In addition, four studies evaluated UDCA in the prevention of DILI: one pilot study, two randomized clinical trials (RCT) and one retrospective study. Three of these studies observed a lower percentage of patients with an increase in transaminases in the groups that used UDCA for DILI prevention. Conclusion: According to available data UDCA seems to have some benefits in the treatment and prevention of DILI. However, the design of the published studies does not allow a firm conclusion to be drawn on the efficacy of UDCA in DILI. A well designed RCT to evaluate the role of UDCA in DILI is needed. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4+ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57:01 transgenic mice (B*57:01-Tg/PD-1−/−). Although AHS is not observed in B*57:01-Tg mice, ABC treatment increases the proportion of cytokine- and cytolytic granule-secreting effector memory CD8+ T cells in CD4+ T cell-depleted B*57:01-Tg/PD-1−/− mice, thereby inducing skin toxicity with CD8+ T cell infiltration, mimicking AHS. Our results demonstrate that individual differences in the immune tolerance system, including PD-1highCD8+ T cells and regulatory CD4+ T cells, may affect the susceptibility of humans to HLA-mediated IDT in humans. Using a transgenic mouse model that recapitulates abacavir hypersensitivity syndrome, an idiosyncratic adverse drug reaction, Susukida et al show that individual differences in the immune tolerance system affect the susceptibility to idiosyncratic drug toxicity. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is commonly understood as an alteration of brain networks, yet case-control analyses against typically-developing controls (TD) have yielded inconsistent results. Here, we devised a novel approach to profile the inter-individual variability in functional network organization and tested whether such idiosyncrasy contributes to connectivity alterations in ASD. Studying a multi-centric dataset with 157 ASD and 172 TD, we obtained robust evidence for increased idiosyncrasy in ASD relative to TD in default mode, somatomotor and attention networks, but also reduced idiosyncrasy in lateral temporal cortices. Idiosyncrasy increased with age and significantly correlated with symptom severity in ASD. Furthermore, while patterns of functional idiosyncrasy were not correlated with ASD-related cortical thickness alterations, they co-localized with the expression patterns of ASD risk genes. Notably, we could demonstrate that patterns of atypical idiosyncrasy in ASD closely overlapped with connectivity alterations that are measurable with conventional case-control designs and may, thus, be a principal driver of inconsistency in the autism connectomics literature. These findings support important interactions between inter-individual heterogeneity in autism and functional signatures. Our findings provide novel biomarkers to study atypical brain development and may consolidate prior research findings on the variable nature of connectome level anomalies in autism. Benkarim et al devise an approach to profile inter-individual variability in functional network organization and test whether such idiosyncrasy contributes to the connectivity alterations found in Autism Spectrum Disorder. Their approach provides potential biomarkers to study atypical brain development and may be used to consolidate prior research findings on the variable nature of connectome level anomalies in autism. [ABSTRACT FROM AUTHOR]

The business model canvas is a popular tool used to develop value-driven business models. Specific emphasis is placed on understanding what customers value and providing users with steps on how to design and deliver value for their customers. In health care, creating and delivering value for patients is an often-discussed topic, with the provision of patient-centered care becoming a standard for many health care organizations. While patients play a key role in determining value, providers are the key to delivering value. Therefore, effective health care management relies on integrating multiple perspectives from key stakeholders. This process requires consideration of the key needs that must be addressed, the resources and capabilities necessary to meet these needs, and the interests and values specific to each set of stakeholders. The business model canvas lends itself well to health care service planning as it incorporates the factors described above into the business model's conceptualization and subsequent realization. This article outlines how the business model canvas was applied to assess the needs of physician stakeholders to help guide the expansion of a pharmacogenomic-based precision medicine clinic that conducts genetic testing for patients at risk of experiencing adverse drug reactions. The article provides a detailed description of how the business model canvas was used and adapted to understand physician's responsibilities and challenges related to drug prescription and dosing, and how the clinic could address physician needs and create value by mapping clinic services onto physician needs and wants. Interviews were conducted with physicians and the data were analyzed following the recommendations of the developers of the business model canvas. The article examines the strengths and limitations of the business model canvas and discusses its applicability to a health care setting. [ABSTRACT FROM AUTHOR]

Alleles of the human leukocyte antigen (HLA) system have been associated with the occurrence of idiosyncratic adverse drug reactions (ADRs). Accordingly, it is assumed that pre‐emptive testing for the presence of certain HLA alleles (HLA‐typing) could prevent these ADRs in carriers. In order to perceive the current evidence for HLA‐associated ADRs, we conducted a scoping review according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). The literature search on PubMed and on Embase was carried out on the July 8 and 9, 2020, respectively. To be included in the scoping review, the studies had to investigate an association of any HLA‐associated ADR with any small molecule approved and available on the Swiss market. We considered English and German primary literature published since 2002. A total of 149 studies were included, whereof most were retrospective, whereas one was a prospective randomized controlled trial. The majority of the studies (n = 33) described the association of HLA‐B*15:02 with carbamazepine. It was not possible to directly compare the studies, as they were too heterogeneous in terms of the ADR definition, the HLA alleles, the number of participants, and the study types. Therefore, we summarized the results in a descriptive manner. Even if an interpretation of the outcomes remains open, the descriptive overview revealed the prevailing complexity and uncertainty in the field. For the future, consistent definitions on the different phenotypes need to be established and applied and the reporting of association studies should follow a harmonized structure. [ABSTRACT FROM AUTHOR]

Background: The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response. Objective: To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance. Methods: A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human in vitro models. Results: Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as "other." Conclusions: Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit. [ABSTRACT FROM AUTHOR]

Drug-induced agranulocytosis is a life-threatening side effect that usually manifests as a severe form of neutropenia associated with fever or signs of sepsis. It can occur as a problem in the context of therapy with a wide variety of drug classes. Numerous drugs are capable of triggering the rare idiosyncratic form of agranulocytosis, which, unlike agranulocytosis induced by cytotoxic drugs in cancer chemotherapy, is characterised by "bizzare" type B or hypersensitivity reactions, poor predictability and a mainly low incidence. The idiosyncratic reactions are thought to be initiated by chemically reactive drugs or reactive metabolites that react with proteins and may subsequently elicit an immune response, particularly directed against neutrophils and their precursors. Cells or organs that exhibit specific metabolic and biotransformation activity are therefore frequently affected. In this review, we provide an update on the understanding of drug-induced idiosyncratic agranulocytosis. Using important triggering drugs as examples, we will summarise and discuss the chemical, the biotransformation-related, the mechanistic and the therapeutic basis of this clinically relevant and undesirable side effect. [ABSTRACT FROM AUTHOR]

Theoretical studies suggest that several mechanisms underlie human visual aesthetic experiences: perceptual processing, which has small variability among individuals (shared properties) and strong correlation with image statistics (e.g. color statistics); cognitive processing, which is idiosyncratic and has weak correlation with image statistics; and emotional processing, which determines the affective part of the aesthetic experience. Furthermore, several experimental studies have reported that the visual aesthetic experience can be largely explained by only a few latent factors. However, it is unclear whether the idiosyncrasy and sensitivity to the image statistics of the latent factors from empirical studies are consistent with the multi-stage processing hypothesis from theoretical studies. In the present study, using exploratory factor analysis, we derived three latent factors of visual aesthetic experiences from participants observing landscape paintings and photographs. Then we examined the difference in the idiosyncrasy of the factors and the relationship between the factors and color statistics. We found that there were significant correlations among the color statistics and Factors 1 and 3, which had a small variance of factor scores (low idiosyncrasy), and no or weak correlation among the color statistics and Factor 2, which had a large variance of factor scores (high idiosyncrasy). Our results provide experimental evidence for the perceptual and cognitive processing of visual aesthetic experiences. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are themost common classes of agents to causeDILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presentingwith suspected DILI.DILI carries amortality rate up to10%when hepatocellular jaundice is present. Patientswith DILI who develop progressive jaundicewith orwithout coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic and rare drug reaction that can be severe and life-threatening if untreated. We present a 34 year old male patient, who developed DRESS syndrome after receiving phenytoin for 8 weeks and presented with rapidly progressive erythematous rash on trunk, face and upper extremities, fever and facial swelling. Abnormal laboratory findings, RegiSCAR score, and Naranjo's probability scale revealed the association between phenytoin and DRESS syndrome. Phenytoin was withdrawn and adequately managed with systemic corticosteroids, antihistamine, and other symptomatic treatments. DRESS syndrome can be cured completely by early detection and removal of culprit drug along with other adequate symptomatic treatments. [ABSTRACT FROM AUTHOR]

Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be 1 factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general. [ABSTRACT FROM AUTHOR]

Introduction: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9Is) were associated with a risk of neurocognitive adverse drug reactions (ADRs). Objective: We aimed to investigate the occurrence of neuropsychiatric ADRs related to PCSK9Is. Methods: We analyzed Individual Case Safety Reports (ICSRs) sent through the European pharmacovigilance database that reported alirocumab or evolocumab as the suspected drug and at least one neurological or psychiatric ADR. The reporting odds ratio (ROR) was computed to compare the probability of reporting ICSRs with neuropsychiatric ADRs between alirocumab, evolocumab and statins. Results: Overall, 2041 ICSRs with alirocumab and/or evolocumab as the suspected drug described the occurrence of neuropsychiatric ADRs. The most reported preferred terms for both drugs were headache, insomnia and depression. No difference between alirocumab and evolocumab was observed for the RORs of ICSRs with ADRs belonging to the System Organ Classes (SOCs) 'Nervous system disorders' or 'Psychiatric disorders' (ROR 1.02, 95% confidence interval 0.91–1.14; and 1.12, 95% CI 0.94–1.34, respectively), while evolocumab and alirocumab had a higher reporting probability of ICSRs with ADRs belonging to the SOC 'Nervous system disorders' compared with atorvastatin and fluvastatin. A lower reporting probability was instead found for ICSRs with ADRs belonging to the SOC 'Psychiatric disorders' for evolocumab and alirocumab versus simvastatin, pravastatin and rosuvastatin. Conclusion: Our results demonstrated that 22.7% of all ICSRs reporting alirocumab or evolocumab as suspect drugs described the occurrence of neuropsychiatric ADRs. The ROR showed that evolocumab and alirocumab had a higher reporting probability of neurological ADRs compared with statins. Further data from real-life contexts are needed. [ABSTRACT FROM AUTHOR]

Fixed drug eruption (FDE) is characterized by the development of well-demarcated erythematous to violaceous plaques, within minutes to hours of the intake of an offending drug. It is known as "fixed" because subsequent exposure to the implicated drug leads to the development of lesions at the same sites that were involved at the time of the previous drug exposure. Fluconazole, a widely used antifungal agent, has a good safety profile, and limited data exist on the development of bullous FDE due to fluconazole. Herein, we report a series of two cases presenting with a generalized bullous FDE (GBFDE), following the consumption of fluconazole. A temporal correlation, typical morphological features, symptoms, and a past history of FDE due to fluconazole were essential clues to the diagnosis. Furthermore, we utilized the Naranjo adverse drug reaction probability scale for causality assessment. Discontinuation of the drug was followed by the resolution of lesions in 7-10 days. GBFDE is an uncommon entity and requires immediate diagnosis as well as prompt discontinuation of the offending agent to minimize the complications. [ABSTRACT FROM AUTHOR]

Introduction: Polypharmacy, as in using multiple medications simultaneously, has become increasingly more common in older patients. Even though pharmacotherapy is essential for managing multiple concurrent chronic conditions, the potential consequences of polypharmacy warrant careful consideration.This paper aims to discuss the consequences of polypharmacy in older adults. Search Method: For this narrative review, PubMed, Scopus, CINAHL, Web of Science, EMBASE, PsycINFO, Proquest, and Age Line databases have been used to search articles relating to the consequences of polypharmacy in older adults. We limited our search to articles published in English between 2010 and 2022. A total of 500 materials were initially identified to be relevant for the review but at the end, only 30 articles were found to match the inclusion criteria. Results: This narrative review examines the multifaceted consequences of polypharmacy in older adults, encompassing adverse drug reactions, drug-drug interactions, medication non-adherence, cognitive impairment, falls and fractures, and overall quality of life. The aim is to raise awareness among healthcare providers about the importance of optimizing medication regimens to mitigate these effects. Conclusion: Polypharmacy in older adults has a broad spectrum of consequences; impacting individual patients, healthcare systems, and society. Recognizing and mitigating the risks associated with polypharmacy is vital for optimizing medication use and promoting healthier aging. This review highlights the importance of a patient-centered approach, regular medication reviews, and interdisciplinary collaboration to ensure that medication regimens align with the goals and preferences of older adults and underscores the need for healthcare providers to critically assess and optimize medication regimens in older adults to mitigate the consequences of polypharmacy. By adopting evidence-based strategies, healthcare professionals can enhance medication safety, improve therapeutic outcomes, and enhance older adults' overall well-being and quality of life. [ABSTRACT FROM AUTHOR]