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Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population‐specific factors (e.g., more frequent use of off‐label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life‐cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post‐marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record‐linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life‐cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs. [ABSTRACT FROM AUTHOR]

Objective: Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time. Methods: A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Summary: Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting. Conclusion: Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug‐induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work‐up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section. [ABSTRACT FROM AUTHOR]

Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs). This article summarises a set of strategies designed to monitor and manage lorlatinib-related AEs that were agreed upon by a multidisciplinary panel of specialists in a meeting held in July 2020. Among the recommendations hereby described, special emphasis was placed on communication: prescribing physicians should inform patients and their families/caregivers about the likelihood and nature of lorlatinib AEs, encouraging them to report any symptoms, while at the same time reassuring them that most events are manageable and resolve spontaneously and have little to no interference with cancer treatment. Importantly, all patients should undergo a set of baseline assessments, including biochemical analysis, evaluation of cardiovascular risk, electrocardiogram (ECG), neurological evaluation and contrast-enhanced magnetic resonance imaging of the brain, which should be repeated regularly during lorlatinib treatment. Supportive medications to treat or relieve lorlatinib AEs were also discussed, as were the conditions requiring specialist consultations and/or adjustments in lorlatinib therapy. The overall goal of this article is to serve as a practical guide for oncologists to systematically and effectively approach lorlatinib AEs. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID‐19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off‐label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off‐label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease. [ABSTRACT FROM AUTHOR]

Introduction: The use of opioids such as morphine has anti-pain effects along with some side effects on body organs. Opioids such as morphine can be transferred from mother to child through the placenta and or breastfeeding. This study aimed to assess the effect of morphine on mineral content and histological changes of incisor teeth of rats born to morphine-addicted mothers. Methods: In this experimental animal study, 24 pregnant rats were randomly divided into 6 groups of control, morphine, zinc, vitamin D, morphine plus zinc, and morphine plus vitamin D. After completion of the breastfeeding period, two babies were randomly selected among the newborns of each mother rat. Mineral content was analyzed using the Rontec device. The obtained data were analyzed by Newman-Keuls multiple comparisons test in Prism 5. Results: Results showed a significant reduction in fluorine content in the experimental groups compared with the control group (P<0.05). The magnesium content in the experimental groups was significantly higher than that in the control group (P<0.05). Microscopic assessment of the slides showed a significantly less enamel maturation in the experimental groups compared with the control group (P<0.05). Conclusion: Morphine use by mothers decreased the fluorine content of tooth structure and retarded the maturity of the enamel of infants. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell–mediated reactions classically occur more than 6 hours after drug administration and include life‐threatening conditions such as toxic epidermal necrolysis, Stevens‐Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA‐B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA‐compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim‐sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future. [ABSTRACT FROM AUTHOR]

In recent years, 3D bioprinting technology has developed rapidly, becoming an essential tool in the fields of cancer research, tissue engineering, disease modeling and mechanistic studies. This paper reviewed the fundamental principles of bioprinting technology and its current applications in cancer research and tissue engineering. Bioprinting is an additive manufacturing technology that constructs complex three-dimensional tissue structures by digitally controlling the layer-by-layer deposition of biomaterials and living cells. The core steps of bioprinting include designing a 3D model, selecting appropriate bioprinting techniques and materials, printing layer by layer, followed by post-processing involving cell culture and functionalization. In cancer research, 3D bioprinting can create complex tumor models that simulate the tumor microenvironment, revealing new mechanisms of tumor initiation and progression. Traditional in vitro models, such as 2D cell cultures or animal models, often fail to accurately replicate the complexity of human tumors. However, 3D bioprinted tumor models, which mimic the dynamic interactions between tumor cells and their environment such as immune cells, stroma and blood vessels, offer a more biomimetic platform for studying tumor growth, invasion and metastasis. These models provide a research platform that closely mirrors actual tumor behavior. Additionally, Bioprinted models and scaffolds can be leveraged in personalized precision therapies by efficiently constructing patient-specific 3D models from their own cells. These models enable the prediction of patient’s sensitivity to drugs and radiotherapy. Additionally, localized scaffolds can be developed to meet individual patient needs, allowing for the formulation of appropriate drug types and dosages. Furthermore, 3D-printed scaffolds can support drug delivery by targeting specific areas, reducing drug-related side effects. They can also be used to facilitate local immunotherapy, cytokine therapy, cancer vaccines, and chimeric antigen receptor cell therapy, enhancing therapeutic outcomes. In tissue engineering, traditional tissue repair methods often struggle to address the complex requirements of constructing intricate tissue structures. 3D bioprinting offers a novel solution by enabling the creation of complex tissue architectures and promoting tissue regeneration. Basic tissues, such as bone, cartilage and skin, which have higher regenerative capacities, are gradually being incorporated into clinical practice. Significant progress has also been made in the repair and reconstruction of more complex organs like the liver and heart, though considerable challenges remain before these advancements can be fully translated into clinical applications. Finally, this paper discussed the current challenges and future directions of 3D bioprinting in these fields, aiming to provide reference for researchers. [ABSTRACT FROM AUTHOR]

Introduction: Smartphone applications (apps) for pharmacovigilance present an opportunity for integration as cost-effective healthcare service intervention into basic healthcare services in low-resource settings. This study aimed to (i) evaluate the implementation of the Med Safety app in Burkina Faso, and (ii) compare the characteristics of the reports sent by the Med Safety app with those sent on paper form. Methods: The study had two components: (i) a cross-sectional online survey assessing the Med Safety app, and (ii) a retrospective analysis comparing the characteristics of the Med Safety reports with those of the paper form, received by the National Pharmacovigilance Centre of Burkina Faso (CNVPS), from January 1, 2021 to December 31, 2022. We evaluated the success of the implementation of the Med Safety intervention using measures of acceptability, usefulness and feasibility. This assessment involved a set of 14 items rated on a 4-point Likert scale. Acceptability, feasibility, and usefulness were determined based on achieving a total score higher than the mean. Subsequently, we computed the proportion of participants whose overall score for all items exceeded the mean. Continuous and categorical variables were compared using the Wilcoxon rank-sum test and the Chi2 test, respectively. The significance level of the statistical test was set at 5%. Results: The survey participation rate was 51.9% (160/308). Half of the respondents were in the 35-44 age group (50.6%), and participants were predominantly male (71.9%). The Med Safety app was acceptable, feasible, and useful to 58.1% of respondents. The most useful features of the app were "reporting" (53.1%), "news" (13.6%) and "watch list" (12.4%). During the period, a total of 1,472 reports were received, including 357 (24.3%) through Med Safety and 1,115 (75.7%) through the paper form. The reports of adverse events following immunization received at the CNVPS numbered 974 (66.2%), these were related to COVID-19 vaccines, with 256 (26.3%) through the Med Safety and 718 (73.7%) through the paper form. The median time to submit the reports to the CNVPS was 159 (IQR 59–187) days for the Med Safety and 166 (IQR 107–281) days for the paper form (p < 0.001). Conclusion: In Burkina Faso, the Med Safety was found to be acceptable, useful, and feasible by users surveyed. In addition, and compared to the paper form, the app reduces the time to submit a report, and with increase in use, the reporting timeframe could be further improved. [ABSTRACT FROM AUTHOR]

The article focuses on the glucocorticoids being a risk factor causing osteoporosis in patients with immune thrombocytopenia (ITP) receiving steroids. It talks about the Good Practice Paper compiled by the British Society for Haematology (BSH) consisting of guideline for the prevention of glucocorticoid-induced osteoporosis (GIO) during the treatment of patients with ITP.

Drug hypersensitivity reactions (DHR) constitute a major and common public health problem, particularly in children. One of the most severe manifestations of DHR is anaphylaxis, which might be associated with a life‐threatening risk. During those past decades, anaphylaxis has received particularly a lot of attention and international consensus guidelines have been recently published. Whilst drug‐induced anaphylaxis is more commonly reported in adulthood, less is known about the role of drugs in pediatric anaphylaxis. Betalactam antibiotics and non‐steroidal anti‐inflammatory drugs are the most commonly involved drugs, probably related to high prescription rates. Diagnosis relies on the recognition of symptoms pattern and is based on complete allergic workup, particularly including skin tests and/or specific IgE. However, the real diagnostic value of those tests to diagnose immediate reactions in children remains not well defined for a significant number of the drugs. Generally, a drug provocation test is discussed to confirm or exclude an immediate‐onset drug‐induced hypersensitivity. Although avoidance of the incriminated drug (and related drug) is the rule, rapid desensitization is useful in selected subgroups of patients. There is a need for large, multicentric studies, to evaluate the real diagnostic value of the currently available skin tests. Moreover there is also a need to develop new diagnostic tests in the future to improve the management of these children. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility; however, whether women with PCOS and spontaneous or drug-induced ovulatory cycles have the same reproductive potential as non-PCOS controls is a matter of debate. In the present opinion paper, the author takes the opportunity to summarize the collective evidence supporting the hypothesis of reduced fertility potential in women with PCOS, regardless of ovulatory status, and speculate that reduced reproductive potential may be caused by altered oocytes, embryo and endometrial competence, and infertility-related co-morbidities as well as an increased risk of pregnancy complications. [ABSTRACT FROM AUTHOR]

Background: Recommended since 2012 by the World Health Organization (WHO), seasonal malaria chemoprevention (SMC) is a community-based intervention to prevent malaria in children in African regions where malaria transmission follows a seasonal pattern. Following the publication of consolidated WHO guidelines for malaria, SMC is expected to reach more children in new geographies in future years. Though SMC has been shown to reduce malaria-related morbidity and mortality, there is potential for quality improvement of the intervention implementation. Assisted by ten quality standards from a framework developed by Malaria Consortium, this paper aims to better understand the quality of SMC implementation and identify potential barriers to quality delivery of SMC. Methods: A qualitative thematic analysis on data collected after the annual SMC rounds implemented in Burkina Faso and Chad in 2019 was conducted. Sixteen focus group discussions conducted with caregivers and community distributors were analysed. Three selected quality standards for SMC delivery; planning and enumeration; community engagement; and administration of SMC medicines provided overarching quality themes under which subthemes were identified. Results: Eight subthemes relating to the three quality standards were identified. Although SMC was well accepted by communities in both settings, common barriers to the quality delivery of SMC were identified including difficulty ensuring adherence to the SMC administration protocol; difficulties reaching mobile populations; concerns around adverse drug reactions; rumours, and concerns about SMC safety; and community distributors' working conditions. Context-specific barriers included: the suboptimal timeliness of the SMC round in Burkina Faso, and the lack of involvement of female caregivers in mobilization activities in Chad. Conclusion: In the context of increased adoption of SMC, this paper provides relevant insights and recommendations for the improved implementation of SMC programmes. These include the integration of strategies addressing communities' concerns around adverse drug reactions, gender-specific mobilization strategies, and attention to community distributors' working conditions. It also highlights the importance and utility of further, robust research on the quality of SMC delivery. [ABSTRACT FROM AUTHOR]

Pharmacogenetics is the study of genetic variants in genes which may impact on the outcome of drug treatment, either through safety considerations (occurrence of adverse drug reactions or therapeutic failure) or altered drug pharmacokinetics. This paper provides a brief history of pharmacogenetics research in the Aotearoa/New Zealand context, and a commentary on our current state. Factors that have limited translation of pharmacogenetic knowledge into ou r healthcare system are considered, and possible solutions to these are proposed. Pharmacogenetic knowledge has long been invoked as a way to improve the safety and success of drug prescribing, but (with some notable exceptions) it has largely failed to achieve this promise. Several barriers to clinical implementation need to be overcome to ensure that pharmacogenetics becomes a key component of precision health for all people in Aotearoa/New Zealand. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) activate T cells, causing immune-related adverse events (irAEs). Skin manifestations are common among irAEs, but ICI-associated bullous pemphigoid (BP) is rare. Inhibiting programmed death (PD)-1 signaling, in addition to causing epitope spreading, may disrupt B and T cell balance, causing excessive autoantibody production against the skin's basement membrane, leading to BP. A 70-year-old woman developed late-onset multi-organ irAEs, including diarrhea, thyroid dysfunction, and BP, while receiving pembrolizumab, a PD-1 inhibitor. This highlights the long-term risk of irAEs, which can occur 2–3 years after starting ICIs. In cases of multi-organ irAE, C-reactive protein levels and neutrophil/lymphocyte ratio are often low. These characteristics were observed in our case. Few papers address multiple organ involvement, highlighting the need to consider irAEs in a multi-organ context. While it is known that drug-induced skin reactions worsen as blood eosinophil counts increase, in our case, the eosinophil count remained normal, suggesting that ICI-associated BP might have been controlled without discontinuing the ICI and through tapering of low-dose oral prednisone treatment. Additionally, in this case, significant CD4-positive T cell infiltration was observed in the immunostaining examination of the blisters, indicating that severe CD4-positive T cell infiltration induced by the ICI might have led to multi-organ involvement, including severe diarrhea. Few reports focus on blood eosinophil counts in BP cases or discuss CD4 and CD8 immunostaining in BP cases. Therefore, future research should explore the relationship between blood eosinophil counts, immunostaining results, and the prognosis of irAEs, including BP, in treatment courses. [ABSTRACT FROM AUTHOR]

Additional risk minimization strategies may be required to assure a positive benefit–risk balance for some therapeutic products associated with serious adverse drug reactions/risks of use, without which these products may be otherwise unavailable to patients. The goals of risk minimization strategies are often fundamentally to influence the behavior of healthcare professionals (HCPs) and/or patients and can include appropriate patient selection, provision of education and counselling, appropriate medication use, adverse drug reaction monitoring, and adoption of other elements to assure safe use, such as pregnancy prevention. Current approaches to additional risk minimization strategy development rely heavily on information provision, without full consideration of the contextual factors and multi-level influences on patient and HCP behaviors that impact adoption and long-term adherence to these interventions. Application of evidence-based behavioral science methods are urgently needed to improve the quality and effectiveness of these strategies. Evidence from the fields of adherence, health promotion, and drug utilization research underscores the value and necessity for using established behavioral science frameworks and methods if we are to achieve clinical safety goals for patients. The current paper aims to enhance additional risk minimization strategy development and effectiveness by considering how a behavioral science approach can be applied, drawing from evidence in understanding of engagement with pharmaceutical medicines as well as wider public health interventions for patients and HCPs. [ABSTRACT FROM AUTHOR]

Aims This paper discusses the application of transformational leadership to the teaching and learning of safe medication management. Background The prevalence of adverse drug events ( ADEs) and medication-related hospitalisations (one hundred thousand each year in the USA) are of concern. Evaluation This discussion is based on a narrative literature review and scrutiny of international nursing research to synthesise pedagogical strategies for the application of transformational leadership to teaching medication safety. Key issues The four elements relating transformational leadership to medication safety education are: 'Idealised influence' or role modelling, both actual and exemplary, 'Inspirational motivation' providing students with commitment to medication safety, 'Intellectual stimulation' encouraging students to value improvement and change, and 'Individualised consideration' of individual students' educational goals, practice development and patient outcomes. The model lends itself to experiential learning and a case-study approach to teaching, offering an opportunity to reduce nursing's theory-practice gap. Conclusion Transformational leadership for medication safety education is characterised by a focus on the role of nurse educators and mentors in the development of students' abilities, creation of a supportive culture, and enhancement of students' creativity, motivation and ethical behaviour. This will prepare nursing graduates with the competencies necessary to be diligent about medication safety and the prevention of errors. Implications for nursing management Teaching medication safety through transformational leadership requires the close collaboration of educators, managers and policy makers. Investigation of strategies to reduced medication errors and consequent patient harm should include exploration of the application of transformational leadership to education and its impact on the number and severity of medication errors. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute promyelocytic leukemia (APL) stands as a remarkable success in achieving high cure rates with chemotherapy-free treatment regimens. Despite these remarkable outcomes, hematologists managing patients with APL take into consideration the distinct side effects associated with the two dual differentiation agents, i.e., all-transretinoic acid (ATRA) and arsenic trioxide (ATO). The objective of this paper is to review relevant literature data and discuss the recommended management strategies of non-hematologic early and late complications that arosein patients diagnosed with APL who were treated with ATO and ATRA-based regimens. The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities. [ABSTRACT FROM AUTHOR]

We present a case study of corrupted discourses in medicine. Medicine is a fallible science. Therefore, it is not surprising that mistakes in the assessment of data and early closure of discourse have led to a highly biased view of the Covid-19 crisis. We present two examples of papers which were retracted following criticisms and republished after a lengthy re-reviewing process. One paper discussed the clinical benefits of COVID-19 vaccinations and the potential risk profile of these vaccinations using the Dutch Adverse Drug Reaction Register. The results of this study were not very favorable. The pressure mounted on the publisher of the journal Vaccines (MDPI, Basel) was huge, and the paper was retracted, although none of the classical reasons for retraction were present. The second paper was about carbon dioxide content in inhaled air under face masks in children, which revealed amounts of CO2 inhaled under masks that violate accepted security norms by a factor of six. This paper was also retracted after criticisms were raised online and after a very dubious re-review process. A closer analysis shows that both retractions were politically motivated. We analyze these case studies and conclude that in the era of COVID-19, politics and financial incentives are increasingly replacing scientific discourse. The profit motive in scientific discourse has opened the floodgates to political influences. This makes obvious what has long been a problem: Financial conflicts of interest continue to distort research and play a major role in evaluations of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

This review paper aims to provide an overview of chronomodulated drug delivery systems for the treatment of hypertension. Hypertension is a chronic medical condition that affects millions of people worldwide, and effective treatment is crucial to prevent complications such as heart disease and stroke. Chronomodulated drug delivery utilises the concept of circadian rhythms to optimise drug efficacy and minimise side effects. The paper examines various chronomodulated drug delivery approaches, including pulsatile, delayed-release, and chronopharmaceutical systems, highlighting their advantages and limitations. Furthermore, the potential future developments in this field are discussed, emphasising the importance of personalised medicine and the integration of wearable technology for real-time monitoring and drug administration. Overall, this review provides valuable insights into the potential of chronomodulated drug delivery systems for improving patient outcomes and minimising side effects. By utilising chronomodulated drug delivery approaches, healthcare professionals can ensure that medications are released at specific times when they are most effective, thereby maximising their therapeutic benefits. Pulsatile drug delivery systems, for example, can mimic the body's natural circadian rhythm, allowing for targeted drug release during periods of peak efficacy. Delayed-release systems, on the other hand, can help reduce side effects by delivering drugs to specific regions of the gastrointestinal tract where they are better tolerated. [ABSTRACT FROM AUTHOR]

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are musclerelated. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term "statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented. [ABSTRACT FROM AUTHOR]

Introduction: There is a need to strengthen the evidence base regarding medication use during pregnancy and to facilitate the early detection of safety signals. EudraVigilance (EV) serves as the primary system for managing and analysing information concerning suspected adverse drug reactions (ADRs) within the European Economic Area. Despite its various functionalities, the current format for electronic submissions of safety reports lacks a specific data element indicating medicine exposure during pregnancy. Objective: This paper aims to address the limitations of existing approaches by developing a rule-based algorithm in EV that more reliably identifies cases that are truly representative of an ADR during pregnancy. Methods: The study utilised the standardised MedDRA query (SMQ) 'Pregnancy and neonatal topics' (PNT) as a benchmark for comparison. Recognising that the SMQ PNT also retrieves healthy pregnancy outcomes, contraceptive failure, failed abortifacients as well as ADRs not associated with pregnancy, a novel algorithm was tailored to improve the accuracy of identifying suspected ADRs occurring during pregnancy. Results: Upon testing, the algorithm demonstrated superior performance, correctly predicting 90% of cases reporting an ADR during pregnancy, compared to 54% achieved by the SMQ PNT. The implementation of the algorithm in EV led to the retrieval of 202,426 cases. Conclusion: The development and successful testing of the novel algorithm represents a step forward in pregnancy-specific signal detection in EV. Because signals associated with pregnancy may be diluted in a large database such as EV, this study lays the groundwork for future research to evaluate the effectiveness of disproportionality methods on a more refined subset of pregnancy-related ADR reports. [ABSTRACT FROM AUTHOR]

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies. [ABSTRACT FROM AUTHOR]

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment. [ABSTRACT FROM AUTHOR]

Reporting adverse drug reactions (ADRs) is fundamental in improving medication safety. Community pharmacists (CPs) being the first point of contact for individuals seeking healthcare in a community, play a significant role in ADR reporting. However, this has been poorly implemented in many countries including Nigeria. This paper aims to explore stakeholders' perspectives on current reporting practices and suggest ways to enhance ADR reporting among CPs in Nigeria. This qualitative study employed a purposive sampling approach to identify key informants. Key informant interviews (KIIs) were conducted with 25 carefully selected pharmacists, using a semi-structured interview guide between July 2023 and August 2023. The interview transcripts were analyzed using a thematic content approach. While a low ADR reporting trend was observed among all participating pharmacists, it was notably higher among those with less than five years of experience. The main barriers to ADR reporting, as identified by the interviewed community pharmacists were lack of awareness and knowledge, absence of motivation, and insufficient feedback from National Agency for Food Drug Administration and Control (NAFDAC). Training and awareness campaigns were the most frequently suggested methods for improving ADR reporting. Other proposed strategies included providing motivation, regular feedback, establishing mandatory reporting, and simplifying the reporting process. The study has highlighted the suboptimal ADR reporting practices among CPs in Anambra state. It underscores the significance of training, sensitization, advocacy, and other related interventions as pivotal means to enhance ADR reporting in this group. Furthermore, there is a pressing need for intervention-based studies to delve into and implement these approaches effectively. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is a chronic metabolic disease with a steadily increasing prevalence worldwide. Diabetes affects the function of many organs, including the skin. Pharmacotherapy for T2DM is mainly based on oral hypoglycemic drugs. The therapeutic strategy is chosen taking into account the individual patient's characteristics, among other comorbidities. Antidiabetic drugs can induce cutaneous adverse reactions (CADRs) ranging in severity from mild erythema to serious disorders such as DRESS or Stevens–Johnson syndrome. CADRs can result from hypersensitivity to the drug but can also be related to the mechanism of action of the drug or cross-reactivity with drugs of similar structure. This paper reviews CADRs induced by oral antidiabetic drugs, considering their dermatological manifestations and possible pathomechanisms. Particular attention was paid to specific dermatological conditions such as dipeptidylpeptidase 4 inhibitor-associated bullous pemphigoid or Fournier's gangrene associated with sodium-glucose cotransporter 2 inhibitor therapy. Knowledge of the dermatological manifestations of CADRs is important in clinical practice. Recognition of a skin lesion resulting from an adverse drug reaction allows for appropriate management, which in this case is primarily related to drug discontinuation. This is particularly important in the treatment of T2DM since this disease has a high prevalence in the elderly, who are at higher risk of adverse drug reactions. [ABSTRACT FROM AUTHOR]

A drug's pharmacokinetic (PK) profile will determine its dose and the frequency of administration as well as the likelihood of observing any adverse drug reactions. It is important to understand these PK properties as early as possible in the drug discovery process, ideally, to accurately predict these prior to synthesising the molecule leading to significant improvements in efficiency. In this paper, we describe the approaches used within AstraZeneca to improve our ability of predicting the preclinical and human pharmacokinetic profiles of novel molecules using machine learning and artificial intelligence. We will show how combining chemical structure-based approaches with experimentally derived properties enables improved predictions of in vivo pharmacokinetics and can be extended to molecules that go beyond the classical Lipinski's rule-of-five space. We will also discuss how combining these in vitro and in vivo predictive models could ultimately improve our ability to predict the human outcome at the point of chemical design. [ABSTRACT FROM AUTHOR]

Background: Potentially inappropriate polypharmacy (PIP) is among the major factors leading to adverse drug reactions, increased healthcare costs, reduced medication adherence, and worsened patient conditions. This study aims to identify existing interventions implemented to monitor and manage polypharmacy in the Italian setting. Methods: A systematic literature review (PROSPERO: CRD42023457049) was carried out according to the PRISMA statement guidelines. PubMed, Embase, ProQuest, and Web of Science were queried without temporal constraints, encompassing all published papers until October 2023. Inclusion criteria followed the PICO model: patients with polypharmacy; interventions to monitor/manage polypharmacy regimen versus no/any intervention; outcomes in terms of intervention effectiveness and cost variation. Results: After duplicate deletion, 153 potentially relevant publications were extracted. Following abstract and full-text screenings, nine articles met the inclusion criteria. Overall, 78% (n = 7) were observational studies, 11% (n = 1) were experimental studies, and 11% (n = 1) were two-phase studies. A total of 44% (n = 4) of the studies involved patients aged ≥ 65 years, while 56% (n = 5) were disease-specific. Monitoring was the most prevalent choice of intervention (67%; n = 6). Outcomes were mainly related to levels of polypharmacy (29%; n = 6) and comorbidities (29%; n = 6), effectiveness rates (14%; n = 3), and avoidable costs (9%; n = 2). Conclusions: This review outlines that Italy is still lacking in interventions to monitor/manage PIP, addressing an unmet need in developing patient-tailored strategies for reducing health-system burden. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus. AD is harmful to both children and adults, but its pathogenic mechanism has yet to be fully elucidated. The development of mouse models for AD has greatly contributed to its study and treatment. Among these models, the exogenous drug-induced mouse model has shown promising results and significant advantages. Until now, a large amount of AD-related research has utilized exogenous drug-induced mouse models, leading to notable advancements in research. This indicates the crucial significance of applying such models in AD research. These models exhibit diverse characteristics and are highly complex. They involve the use of various strains of mice, diverse types of inducers, and different modeling effects. However, there is currently a lack of comprehensive comparative studies on exogenous drug-induced AD mouse models, which hinders researchers' ability to choose among these models. This paper provides a comprehensive review of the features and mechanisms associated with various exogenous drug-induced mouse models, including the important role of each cytokine in AD development. It aims to assist researchers in quickly understanding models and selecting the most suitable one for further investigation. [Display omitted] • Exogenous-drugs induced mouse models are very helpful in studying the pathogenesis of AD in humans. • Hapten-induced mouse models are cost-effective but time-consuming. • OVA-induced mouse models are widely applicable. • MC903-induced mouse models are ideal for rapid AD modelling. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a common clinical pharmacogenic disease. In the United States and Europe, DILI is the most common cause of acute liver failure. Drugs can cause hepatic damage either directly through inherent hepatotoxic properties or indirectly by inducing oxidative stress, immune responses, and inflammatory processes. These pathways can culminate in hepatocyte necrosis. The role of the gut microecology in human health and diseases is well recognized. Recent studies have revealed that the imbalance in the gut microecology is closely related to the occurrence and development of DILI. The gut microecology plays an important role in liver injury caused by different drugs. Recent research has revealed significant changes in the composition, relative abundance, and distribution of gut microbiota in both patients and animal models with DILI. Imbalance in the gut microecology causes intestinal barrier destruction and microorganism translocation; the alteration in microbial metabolites may initiate or aggravate DILI, and regulation and control of intestinal microbiota can effectively mitigate drug-induced liver injury. In this paper, we provide an overview on the present knowledge of the mechanisms by which DILI occurs, the common drugs that cause DILI, the gut microbiota and gut barrier composition, and the effects of the gut microbiota and gut barrier on DILI, emphasizing the contribution of the gut microecology to DILI. [ABSTRACT FROM AUTHOR]

Background: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease in India. Methods and findings: We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. Conclusions: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps—particularly regarding TB care for children or in the private sector—to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade. Tulip A. Jhaveri and team report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for tuberculosis disease in India. Author summary: Why was this study done?: India has the highest tuberculosis (TB) incidence, accounting for about one-quarter of people with TB disease and nearly one-third of TB deaths globally. Many Indians with TB do not traverse all care stages needed to receive treatment and achieve an optimal long-term outcome, with serial losses of people across these stages referred to as the "care cascade." Understanding why losses of people with TB disease occur across the care cascade is crucial to inform interventions to prevent unfavorable outcomes. What did the researchers do and find?: We conducted 3 systematic searches to identify papers published from 2000 to 2023. We extracted information from these studies on risk factors for unfavorable outcomes for each care cascade gap, as well as reasons reported by people with TB who experienced unfavorable outcomes and were surveyed by researchers. Some factors contributed to losses at multiple care cascade stages, including male sex, older age, poverty-related factors, history of prior TB treatment, lower symptom severity or duration, undernutrition, alcohol use, smoking, and dissatisfaction with health services. Other barriers included: lack of TB knowledge and transportation barriers to clinic contributing to lack of care-seeking (Gap 1), poor accessibility of testing and failure to identify people eligible for testing contributing to non-completion of the diagnostic workup (Gap 2), early deaths from diagnostic delays and poor recording of contact information contributing to losses of people before treatment (Gap 3), lack of TB knowledge and depression contributing to unfavorable treatment outcomes (Gap 4), and medication nonadherence contributing to unfavorable treatment outcomes and TB recurrence (Gaps 4 and 5). What do these findings mean?: Reasons for losses of people with TB disease across the care cascade are complex, vary by care cascade gap, and involve patient- and health system-related barriers. India's TB program should target additional services to people with higher risk of poor outcomes and develop multicomponent interventions to address the diverse challenges faced by people with TB. Study limitations include lack of meta-analyses (i.e., estimation of the average effect of each risk factor by combining findings across studies), and caution is required when applying findings across India's diverse population. [ABSTRACT FROM AUTHOR]

Introduction: Spontaneous reporting of adverse events (AEs) is a mainstay of pharmacovigilance, and an ongoing challenge is how to ensure that more high-quality reports are collected for comprehensive information provision. The Med Safety App, a smartphone-based application, was launched in Nigeria in November 2020 to provide an electronic platform for users to seamlessly report AEs. There has been a paucity of evidence on the use of this application or other mobile applications for reporting adverse drug reactions/AEs following immunization in the Nigerian environment. Objective: The aim of this study was to evaluate the trends in adverse event reporting before and after the introduction of the Med Safety App in Nigeria. Methods: This was a retrospective, observational study using data from the VigiFlow database to compare adverse event reporting in Nigeria before and after the deployment of the Med Safety App. The baseline period was 1st April 2019 to 30th October 2020 and the comparison period was 1st November 2020 to 31st May 2022. We used Vigilance Hub, the back-end system for the Med Safety App, to extract data on App downloads and de-identified user statistics. Data were summarized using descriptive statistics, frequencies and proportions. Quality was assessed by assigning a completeness score to each individual case safety report. The Kruskal–Wallis test was used to test for differences in medians between groups. Results: Following deployment of the App, the Nigerian National Pharmacovigilance Centre recorded an increase in the total number of adverse event reports received in VigiFlow, from 2051 in the baseline period to 18,995 following deployment of the App, with 81.7% of those reported via the Med Safety App. There was a reduction in the proportion of paper-based reporting from 98.4 to 15.7% post-deployment, and direct reporting by consumers increased from 2.7 to 17.6%. Of the 15,526 reports submitted via the App, 15,111 (97.3%) had a completeness score above 70% and 6993 (45%) had a completeness score of 100%. The median completeness score of adverse event reports on the Med Safety App was 6 out of 7. On bivariate analysis using the Kruskal–Wallis test, there was an association between means of reporting and completeness score, and this association was significant, with a p value of 0.0001, which may reflect the validation rules that are applied within the App. Conclusion: Deployment of the Med Safety App increased both the number and quality of adverse event reports; however, more awareness and capacity building are needed to strengthen and sustain reporting on the tool by all categories of healthcare professionals and consumers/patients. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) may trigger autoimmune neurological conditions, including movement disorders (MD). Objectives: The aim of this study was to characterize MDs occurring as immune‐related adverse events (irAEs) of ICIs. Methods: A systematic literature review of case reports/series of MDs as irAEs of ICIs was performed. Results: Of 5682 eligible papers, 26 articles with 28 patients were included. MDs occur as a rare complication of cancer immunotherapy with heterogeneous clinical presentations and in most cases in association with other irAEs. Inflammatory basal ganglia T2/fluid attenuated inversion recovery abnormalities are rarely observed, but brain imaging is frequently unrevealing. Cerebrospinal fluid findings are frequently suggestive of inflammation. Half of cases are associated with a wide range of autoantibodies. Steroids and ICI withdrawal usually lead to improvement, even though some patients experienced relapses or a severe clinical course. Conclusion: MDs are a rare complication of ICIs that should be promptly recognized to offer patients a correct diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Drug induced liver injury, as a sub-type of hepatotoxicity, is rare but practical problem, producing challenges for clinicians. Within the recent two months, two patients with heart failure develop febuxostat-induced acute liver injury during hospital stay. To the best of our knowledge, very few cases of febuxostat-induced hepatotoxicity have been reported up to now. In this paper, two unusual cases of febuxostat-induced acute liver injury are herein described. The medical history, drug treatment, clinical symptoms, liver function tests, diagnosis and prognosis are fully given in this paper. It should be noticed that, two liver injury happen in patients of heart failure with reduced ejection fraction. Whether heart failure is a risk factor of febuxostat related liver injury, deserves further research. This paper reminds the clinicians that more attention should be paid to the acute liver injury caused by febuxostat, and liver function tests are suggested especially for patients of heart failure. [ABSTRACT FROM AUTHOR]

Background: Despite unclear evidence to support the long-term use of antipsychotics to treat challenging (problem) behaviours in people with autism in the absence of a psychiatric disorder, this practice is common. Methods: We conducted a systematic review and meta-analysis of all randomised controlled trials (RCTs) involving antipsychotics for people with autism of all ages, irrespective of the outcomes assessed. We searched seven databases and hand-searched ten relevant journals. Two authors independently screened titles, abstracts and full papers and extracted data using the Cochrane Handbook template. We conducted meta-analyses of outcomes and the rate of adverse events. Results: We included 39 papers based on 21 primary RCTs that recruited 1482 people with autism. No RCT assessed any psychiatric disorder outcome, such as psychoses or bipolar disorder. A meta-analysis of ten placebo-controlled RCTs showed a significantly improved Aberrant Behaviour Checklist-Irritability score in the antipsychotic group with an effect size of −6.45 [95% confidence interval (CI) −8.13 to −4.77] (low certainty). Pooled Clinical Global Impression data on 11 placebo-controlled RCTs showed an overall effect size of 0.84 (95% CI 0.48 to 1.21) (moderate certainty). There was a significantly higher risk of overall adverse effects (p = 0.003) and also weight gain (p < 0.00001), sedation (p < 0.00001) and increased appetite (p = 0.001) in the antipsychotic group. Conclusions: There is some evidence for risperidone and preliminary evidence for aripiprazole to significantly improve scores on some outcome measures among children with autism but not adults or for any other antipsychotics. There is a definite increased risk of antipsychotic-related different adverse effects. [ABSTRACT FROM AUTHOR]

Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963–2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters. [ABSTRACT FROM AUTHOR]

Background: Temporomandibular disorders (TMD) are the main cause of chronic facial pain, and intra‐articular (IA) injections of hyaluronic acid (HA) are commonly performed. Objectives: This umbrella review of systematic reviews aimed at analysing the effectiveness of HA injections on pain and functional outcomes in patients affected by TMD. Methods: PubMed, Cochrane Library and PEDro were systematically searched from inception until 17 January 2023 to identify systematic reviews evaluating the effects on pain and functional outcomes of HA IA injections. PROSPERO registration number: CRD42022382586. Results: Out of 316 papers suitable for title/abstract screening, 18 articles were included in the umbrella review. Thirteen studies included only randomized controlled clinical trials (RCTs). The included systematic reviews reported no statistically significant differences between HA and corticosteroids, whereas platelet derivates seem to have good results in pain relief. The literature did not show severe adverse events, except for mild pain in the site of injection. Concerning the quality assessment of the 18 systematic reviews, 2 (11.11%) had a high quality, 3 (16.67%) a moderate quality, 7 (38.89%) a low quality and 6 (33.33%) a critically low quality. Conclusions: Taken together, findings of this umbrella review showed intriguing effects of IA HA injections in terms of reduction of pain intensity and improvement of functioning in patients affected by TMD. Furthermore, there is no agreement on the effectiveness of a combination of arthrocentesis or arthroscopy with IA HA injections. Although the literature showed these positive results after IA HA injections, the overlapping of primary studies in the systematic reviews included might have affect our results, such as the very low quality of the papers. Thus, further RCTs are needed to confirm the efficacy of IA injections of HA on pain relief in patients with TMD. [ABSTRACT FROM AUTHOR]

Drug overdose claimed more than 100,000 lives in the United States in 2021. Drug‐induced homicide (DIH) laws create specific criminal liability for individuals who provide drugs that cause or contribute to the death of another person. DIH prosecutions in the United States have increased substantially over the past decade despite the absence of meaningful evidence of their individual‐ or community‐level impacts. Recently, Lee et al. analyzed the impact of DIH laws on county‐level opioid overdose mortality across 92 counties in 10 states and concluded that DIH laws are associated with significant reductions in rates of opioid overdose death. In this commentary, we present evidence demonstrating that the Lee et al. study is fundamentally flawed. Specifically, the legal data used by Lee et al. to define their treatment condition (the presence or absence of a state‐level DIH law) is incorrect in almost every aspect. We also describe significant methodological weaknesses, including flawed sampling strategies that resulted in a biased sample of county overdose rates as well as flawed modeling strategies that cannot effectively evaluate the hypothesis that DIH laws negatively impact opioid overdose mortality. More research on the individual‐ and community‐level impacts of DIH laws is needed. In the meantime, we advise policymakers to strengthen state 911 Good Samaritan laws, as DIH laws appear to erode the efficacy of this proven overdose‐prevention strategy. Key points: Drug‐induced homicide laws create specific criminal liability for individuals who provide drugs that cause or contribute to the death of another person and are increasingly used in the United States despite little evidence of their impact on overdose and other harms.This paper critically evaluates a recent paper that analyzed the impact of these laws on county‐level opioid overdose mortality across 92 counties in 10 US states, concluding that these laws are associated with reduced opioid overdose deaths.We present evidence demonstrating that the previous paper is fundamentally flawed, detailing serious errors in the underlying legal research as well as significant methodological weaknesses that render the results of the paper unreliable.Reliable research on the impact of these laws is urgently needed. In the meantime, policymakers are urged to implement policies with robust evidence demonstrating their overdose‐prevention impacts: medications for opioid use disorder, naloxone access, and syringe services programs. [ABSTRACT FROM AUTHOR]

Monitoring for drug-induced liver injury (DILI) via serial transaminase measurements in patients on potentially hepatotoxic medications (e.g., for HIV and tuberculosis) is routine in resource-rich nations, but often unavailable in resource-limited settings. Towards enabling universal access to affordable point-of-care (POC) screening for DILI, we have performed the first field evaluation of a paper-based, microfluidic fingerstick test for rapid, semi-quantitative, visual measurement of blood alanine aminotransferase (ALT). Our objectives were to assess operational feasibility, inter-operator variability, lot variability, device failure rate, and accuracy, to inform device modification for further field testing. The paper-based ALT test was performed at POC on fingerstick samples from 600 outpatients receiving HIV treatment in Vietnam. Results, read independently by two clinic nurses, were compared with gold-standard automated (Roche Cobas) results from venipuncture samples obtained in parallel. Two device lots were used sequentially. We demonstrated high inter-operator agreement, with 96.3% (95% C.I., 94.3–97.7%) agreement in placing visual results into clinically-defined “bins” (<3x, 3–5x, and >5x upper limit of normal), >90% agreement in validity determination, and intraclass correlation coefficient of 0.89 (95% C.I., 0.87–0.91). Lot variability was observed in % invalids due to hemolysis (21.1% for Lot 1, 1.6% for Lot 2) and correlated with lots of incorporated plasma separation membranes. Invalid rates <1% were observed for all other device controls. Overall bin placement accuracy for the two readers was 84% (84.3%/83.6%). Our findings of extremely high inter-operator agreement for visual reading–obtained in a target clinical environment, as performed by local practitioners–indicate that the device operation and reading process is feasible and reproducible. Bin placement accuracy and lot-to-lot variability data identified specific targets for device optimization and material quality control. This is the first field study performed with a patterned paper-based microfluidic device and opens the door to development of similar assays for other important analytes. [ABSTRACT FROM AUTHOR]

Background: Atypical antipsychotic medications have often been used in the treatment of behavioral and psychological symptoms of dementia (BPSD). Recently, the US Food and Drug Administration (FDA) issued new safety information concerning atypical antipsychotic drugs, indicating that their use may increase the risk of cardiovascular adverse events among elderly adults with BPSD. Based on this information, the Japanese Ministry of Health, Labor and Welfare issued a similar warning against the use of atypical antipsychotic drugs licensed in Japan. We then sought to determine whether or not the use of typical antipsychotics should be recommended to replace atypical antipsychotics. In this paper, we discuss the influence of these warnings on the withholding of use of risperidone exemplified in seven case histories. Methods: Seven inpatients who exhibited BPSD received risperidone monotherapy in our hospital. In response to the FDA notice, the atypical antipsychotics used to treat these patients were replaced with typical antipsychotic agents. Results: During the period of risperidone administration, all patients exhibited clinical improvement compared with their baseline results and showed no adverse events. Two of our seven patients developed psychotic exacerbation and exhibited extrapyramidal symptoms coinciding with the replacement of risperidone with conventional antipsychotics. Conclusion: To the best of our knowledge, this is the first clinical report on the influence of the FDA alert on the use of atypical antipsychotics for psychotic symptoms in older patients with dementia in Japan. In two of our seven BPSD cases, there was no benefit from taking conventional antipsychotics. Our results lead to the conclusion that the use of typical antipsychotics should not be recommended to replace atypical antipsychotics. Although close attention should be paid to the FDA alert, clinicians must take into consideration the balance of benefits and risks when evaluating the appropriate use of antipsychotics in older patients with dementia. [ABSTRACT FROM AUTHOR]

To examine how countries differ in attitudes to adverse drug reactions by examining published scientific papers.We searched Ovid EMBASE for publications indexed by the category′therapeutic agents′, and the subcategory′adverse effects′, by country for 43 countries.We counted 1 810 202 papers world-wide regarding therapeutic agents during 14 years, of which 195 154 (10.8%) were included in the adverse effects subcategory. There were substantial differences between countries, not explained by population, economic variation, overall publication rate on therapeutic agents, or the presence of large indigenous pharmaceutical companies.Many local cultural factors influence the ratio of papers on adverse reactions to all drug effects, so it may be difficult to improve their recognition and reporting by international efforts. [ABSTRACT FROM AUTHOR]

This article reviews the regulatory guidelines that provide for the inclusion of recovery groups in toxicology studies, presents the challenges in the design and interpretation of nonclinical recovery studies, and summarizes the best practices for the role of an anatomic pathologist regarding toxicology studies with recovery groups. Evaluating the potential recovery of histopathologic findings induced by a biopharmaceutical requires the active participation of one or more anatomic pathologists. Their expertise is critical in risk assessment regarding the potential for recovery as well as providing scientific guidance in the design and evaluation of studies with recovery groups. [ABSTRACT FROM PUBLISHER]

Adverse drug reactions (ADRs) are a significant problem in children, affecting one in ten children in hospital. Within the community, one in 500 children will experience an adverse drug reaction each year. Pharmacovigilance has been useful in detecting suspected ADRs. However, most ADRs are unreported and often not suspected. Education of health professionals in relation to drug toxicity improves the reporting rate of suspected ADRs. Clinical trials are useful to evaluate the efficacy of drugs. They are, however, not the best way of looking at ADRs where surveillance following the widespread use of a drug is more appropriate. Alongside work by the regulatory agencies, independent investigators have helped collate data. This information has been useful in developing guidelines to prevent further cases of drug toxicity. Greater awareness and understanding of drug toxicity in children should result in more rational prescribing. [ABSTRACT FROM AUTHOR]

Background: The number of non-intubated general anesthesia outside the operating room is growing as the increasing demand for comfort treatment. Non-intubated general anesthesia outside the operating room requires rapid onset of anesthesia, smoothness, quick recovery, and few postoperative complications. Traditional anesthetic regimens (propofol alone or propofol and opioids/dezocine/midazolam, etc.) have severe respiratory and circulatory depression and many systemic adverse effects. In this paper, we compare the effectiveness and safety of propofol and subclinical doses of esketamine with other traditional regimens applied to non-intubated general anesthesia through a systematic review and meta-analysis. Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and Sinomed databases for the period from January 2000 to October 2022. We rigorously screened the literature according to predefined inclusion and exclusion criteria, while risk assessment of the studies was performed using The Cochrane Collaboration's tool, and statistical analysis of the data was performed using RevMan 5.4 software. The main outcome indicators we evaluated were the various hemodynamic parameters and incidence of various adverse effects between the experimental and control groups after induction of anesthesia. Results: After a rigorous screening process, a total of 14 papers were included in the final meta-analysis. After risk bias assessment, three of the papers were judged as low risk and the others were judged as having moderate to high risk. Forest plots were drawn for a total of 16 indicators. Meta-analysis showed statistically significant differences in HR' WMD 3.27 (0.66, 5.87), MAP' WMD 9.68 (6.13, 13.24), SBP' WMD 5.42 (2.11, 8.73), DBP' WMD 4.02 (1.15, 6.88), propofol dose' SMD -1.39 (-2.45, -0.33), hypotension' RR 0.30 (0.20, 0.45), bradycardia' RR 0.33 (0.14, 0.77), hypoxemia or apnea' RR 0.45 (0.23, 0.89), injection pain' RR 0.28 (0.13, 0.60), intraoperative choking' RR 0.62 (0.50, 0.77), intraoperative body movements' RR 0.48 (0.29, 0.81) and overall incidence of adverse reactions' RR 0.52 (0.39, 0.70).The indicators that were not statistically different were time to wake up' WMD − 0.55 (-1.29, 0.19), nausea and vomiting 0.84' RR (0.43, 1.67), headache and dizziness' RR 1.57 (0.98, 2.50) and neuropsychiatric reaction' RR 1.05 (0.28, 3.93). The funnel plot showed that the vast majority of studies fell within the funnel interval, but the symmetry was relatively poor. Conclusion: In non-intubated general anesthesia, the combination of subclinical doses of esketamine and propofol did reduce circulatory and respiratory depression, injection pain, and other adverse effects, while the incidence of esketamine's own side effects such as neuropsychiatric reactions did not increase, and the combination of the two did not cause the occurrence of new and more serious adverse reactions, and the combination of the two was safe and effective. Trial registration: PROSPREO registration number: CRD 42022368966. [ABSTRACT FROM AUTHOR]

The article offers information on several studies related to topics including drug effects, genetics, and bone repair. L. A. Fitzpatrick and colleagues study the effect of ronacaleret on bone mineral density (BMD) of postmenopausal women. G. H. Dolmans and colleagues discuss role of WNT signaling to Dupuytren's disease. Moreover, K. A. Alexander and colleagues report on the role of osteal macrophages (osteomacs) in the anabolic response to bone injury.

Background: Second-generation antidepressants dominate the management of major depressive disorder, dysthymia, and subsyndromal depression. Evidence on the comparative benefits and harms is still accruing. Purpose: To compare the benefits and harms of second-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) for the treatment of depressive disorders in adults. Data Sources: MEDLINE, EMBASE, PsychLit, Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007, limited to English-language articles. Reference lists of pertinent review articles were manually searched and the Center for Drug Evaluation and Research database was explored to identify unpublished research. Study Selection: Abstracts and full-text articles were independently reviewed by 2 persons. Six previous good- or fair-quality systematic reviews or meta-analyses were included, as were 155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized, controlled trials of at least 6 weeks' duration. For harms, 35 observational studies with at least 100 participants and follow- up of at least 12 weeks were also included. Data Extraction: Using a standard protocol, investigators abstracted data on study design and quality-related details, funding, settings, patients, and outcomes. Data Synthesis: If data were sufficient, meta-analyses of head-tohead trials were conducted to determine the relative benefit of response to treatment and the weighted mean differences on specific depression rating scales. If sufficient evidence was not available, adjusted indirect comparisons were conducted by using meta-regressions and network meta-analyses. Secondgeneration antidepressants did not substantially differ in efficacy or effectiveness for the treatment of major depressive disorder on the basis of 203 studies; however, the incidence of specific adverse events and the onset of action differed. The evidence is insufficient to draw conclusions about the comparative efficacy, effectiveness, or harms of these agents for the treatment of dysthymia and subsyndromal depression. Limitation: Adjusted indirect comparisons have methodological limitations and cannot conclusively rule out differences in efficacy. Conclusion: Current evidence does not warrant the choice of one second-generation antidepressant over another on the basis of differences in efficacy and effectiveness. Other differences with respect to onset of action and adverse events may be relevant for the choice of a medication. [ABSTRACT FROM AUTHOR]

The liver and kidney are the major detoxifying organs in the human body and play an important role in pharmacokinetics. Drug-induced hepatotoxicity and nephrotoxicity can cause irreversible damage to the liver and kidney and are a major cause of drug failure in later stages. Both animal models and conventional cell culture have a number of limitations, such as animal ethics and gene mismatching and there is an urgent need to develop a new drug toxicity evaluation approach. In this paper, a 3D liver–kidney on a chip with a biomimicking circulating system (LKOCBCS) was constructed to obtain kidney and liver models in vitro for drug safety evaluation. LKOCBCS, which has a parallel circulating system mimicking biological circulation, consists of 3D biomimetic tissue of liver lobules similar to that of the human liver constructed by 3D bioprinting and renal proximal tubule barriers fabricated by ultrafast laser assisted etching. The proposed LKOCBCS facilitates the communication between the liver and the kidney, including the exchange of nutrients, compounds, and metabolites. The results revealed that the glucose concentration and cell metabolism stabilized after 7 days. A dynamically repeated low-dose administration of cyclosporine A (CsA) was fed to the system, and hepatotoxicity and nephrotoxicity were observed on day 3 according to the changes in toxicity markers. The high levels of drug induced biomarkers expressed in LKOCBCS indicate that this system is more sensitive than the monoculture liver chip and it is highly potential in replacing animal models for effective drug toxicity screening. [ABSTRACT FROM AUTHOR]

Background: Spontaneous reporting of adverse drug reactions (ADRs) is essential for the post-marketing safety evaluation of drugs. Therefore, good monitoring of ADRs is vital for strengthening drug supervision, management, and guiding rational drug use. Chinese medical institutions are the primary source of ADR case reports, but the proportion of the reports in grade IIIA hospitals is still low due to serious under-reporting. The 3rd Affiliated Hospital of Chengdu Medical College, Chengdu Pidu District People's Hospital, also has such a problem. Objective: To improve the quantity and quality of ADR reports and enhance the level of pharmacovigilance in hospitals, the Third Affiliated Hospital of Chengdu Medical College, People's Hospital of Chengdu Pidu District experienced 10 years to gradually establish a management model to improve the medical staff's reporting rate of spontaneous reporting of ADRs. The management model is led by clinical pharmacists and combines the PDCA with Teach-back methods. The purpose of this paper is to introduce the management model and discuss its advantages and shortcomings of this model. Methods: This study was conducted at the Third Affiliated Hospital of Chengdu Medical College—Chengdu Pidu District People's Hospital. From 2016, the daily management of reporting, auditing, and data improvement of adverse drug reactions in the hospital was carried out by clinical pharmacists, who used the PDCA method combined with the Teach-back method to continuously improve the reporting program of ADRs in the hospital during 2016–2021. Then, the proportion of spontaneous reports of total, new, and serious ADRs was compared before and after the intervention. Also, we performed a time series analysis using an autoregressive moving average model to assess changes in the total number of spontaneous ADR reports before the intervention (2013–2015), the first intervention (2016–2018), and the second intervention (2019–2021). Results: After the combined PDCA and Teach-back method intervention, the median number of reported ADRs per year increased from 50 (range 37–55) in the pre-intervention period to 88 (range 83–162) in the first intervention period and to 374 in the second (range 312–566). Breakpoint regression analysis of the spontaneous reporting rate of ADRs showed that the instantaneous increase after the first intervention was not statistically significant (P = 0.526). However, the reporting rate of ADRs increased at a month-by-month growth rate during the second intervention compared to the first intervention. Its spontaneous reporting rate improved 1.034 times (P = 0.002). After the second intervention, the spontaneous reporting rate of ADRs transiently increased 6.111-fold (P < 0.001), and the month-to-month growth rate increased 1.024-fold (P < 0.001) again. Conclusion: The management model that combines the PDCA and the Teach-back method significantly improves the reporting rate of adverse drug reactions. [ABSTRACT FROM AUTHOR]

Simple Summary: At present, local eye drops, subconjunctival injection, and systemic administration of corticosteroids are the most common methods to control complications in dogs after phacoemulsification. However, these methods are limited by a high frequency of administration, systemic drug reactions in dogs, poor compliance among owners, and high care requirements. In this study, triamcinolone acetonide was injected into the anterior chambers of dogs after phacoemulsification to observe and evaluate its effects on controlling postoperative complications. The intraocular pressure, corneal edema, aqueous flare, aqueous humor protein concentration, and prostaglandin E2 concentration in these dogs were measured and evaluated at different time points before and after surgery. The findings confirmed that the intracameral injection of triamcinolone acetonide achieved a favorable effect on controlling transient ocular hypertension and corneal edema after phacoemulsification in dogs. Moreover, the intracameral injection of 1.5 mg of triamcinolone acetonide decreased the protein and prostaglandin E2 concentrations in the aqueous humor of dogs after surgery. It was demonstrated that triamcinolone acetonide-based treatment can be safely employed to effectively control common complications after phacoemulsification in dogs. Therefore, this treatment method is worthy of clinical application. The intracameral injection of triamcinolone acetonide (TA) has achieved favorable clinical effects in controlling intraocular inflammatory reactions in humans after cataract surgery. However, the effect of this method remains unclear in veterinary practice. In this paper, 18 dogs with bilateral cataracts were randomly divided into three groups, with 6 dogs in each group. Phacoemulsification and intraocular lens implantation were performed on the 36 eyes of these dogs. A total of 0.1 mL of TA solution was injected into the oculus dexter (OD) anterior chambers. All oculus sinister (OS) anterior chambers of these dogs were used as controls. The results demonstrated that the corneal edema severity scores of the OD (1.5 mg TA) were lower than those of the OS from the 1st to 7th day after surgery, with a significant difference on the 3rd day after surgery (p = 0.033). The corneal edema severity scores in the OD (1.5 mg TA) were significantly lower than those in the OD (0.5 mg TA) on the 3rd day after surgery (p = 0.036). The aqueous humor protein concentration of the OD (1.5 mg TA) had a lower concentration than the OS on the 1st day after surgery (p = 0.004). Furthermore, on the 5th and 10th days, the aqueous humor protein concentration of the OD (1.5 mg TA) was lower than that of the OS (p = 0.038 and p = 0.044, respectively). The aqueous humor PGE2 concentration of the OD (1.5 mg TA) had a lower concentration than the OS on the 1st day after surgery (p = 0.026). The aqueous humor PGE2 concentrations in the OD (1.0 mg TA) and OD (1.5 mg TA) were lower compared to that in the OD (0.5 mg TA) on the 1st day after surgery (p = 0.041 and p = 0.037, respectively). It was demonstrated that TA-based treatment can be safely employed to effectively control common complications after phacoemulsification in dogs. [ABSTRACT FROM AUTHOR]