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Athletes, both amateur and professional, often resort to the consumption of nutritional supplements without professional supervision and without being aware of the risks they may entail. We conducted an exhaustive literature search to determine the most common substances found as contaminants in dietary supplements. For each substance, we analyzed its mechanism of action, clinical indication, health risk, and putative use as doping agent. In addition, we evaluated the current regulation of these supplements. Contamination of nutritional supplements (accidental or intentional), especially with steroids and stimulants, is a hazardous situation. The prolonged consumption of these products without being aware of their composition can cause serious health risks and, in the case of professional athletes, a possible sanction for doping. [ABSTRACT FROM AUTHOR]

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050–10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97–106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050–100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93–106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022. [ABSTRACT FROM AUTHOR]

Understanding the relationship between the concentration of a drug and its therapeutic efficacy or side effects is crucial in drug development, especially to understand therapeutic efficacy in central nervous system drug, quantifying drug-induced site-specific changes in the levels of endogenous metabolites, such as neurotransmitters. In recent times, evaluation of quantitative distribution of drugs and endogenous metabolites using matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) has attracted much attention in drug discovery research. However, MALDI-MSI quantification (quantitative mass spectrometry imaging, QMSI) is an emerging technique, and needs to be further developed for practicable and convenient use in drug discovery research. In this study, we developed a reliable QMSI method for quantification of clozapine (antipsychotic drug) and dopamine and its metabolites in the rat brain using MALDI-MSI. An improved mimetic tissue model using powdered frozen tissue for QMSI was established as an alternative method, enabling the accurate quantification of clozapine levels in the rat brain. Furthermore, we used the improved method to evaluate drug-induced fluctuations in the concentrations of dopamine and its metabolites. This method can quantitatively evaluate drug localization in the brain and drug-induced changes in the concentration of endogenous metabolites, demonstrating the usefulness of QMSI. [ABSTRACT FROM AUTHOR]

Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop indicated for the treatment of Demodex blepharitis. It is the first and currently the only US FDA-approved treatment for this condition. One drop of lotilaner 0.25% instilled in each eye twice daily for 6 weeks was associated with significantly higher rates of collarette reduction to ≤ 2 collarettes (primary endpoint), mite eradication and erythema cure compared to the vehicle control. Lotilaner 0.25% is generally well tolerated, with the most common ocular adverse reaction being instillation site stinging and burning (incidence 10%). The 6-week treatment remained durable with no safety issues during the observational period for up to a year. The eye drop was generally neutral or very comfortable for most patients. Plain Language Summary: Demodex blepharitis is a common eyelid margin disease caused by an infestation of Demodex mites. It is characterized by persistent cylindrical waxy dandruff (collarettes) in the eyelashes, eyelid margin inflammation, redness and eye irritation. Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop that eradicates Demodex mites. It is FDA-approved in the USA for the treatment of Demodex blepharitis. One drop of lotilaner 0.25% in each eye twice daily for 6 weeks significantly reduces collarettes, decreases or eradicates Demodex mites and reduces eyelid redness in patients with Demodex blepharitis. The treatment is generally well tolerated, with the most common ocular adverse reactions being installation site stinging and burning (incidence 10%). Currently, lotilaner 0.25% is the only US FDA-approved treatment for Demodex blepharitis. [ABSTRACT FROM AUTHOR]

The article discusses the integration of artificial intelligence (AI) in clinical pharmacology, highlighting its potential in drug discovery, personalized medicine, and patient care. AI tools can accelerate drug development, identify new drug-target pairs, and optimize clinical trials. While AI offers significant advancements, challenges such as ethical concerns, data biases, and integration hurdles must be addressed. Collaboration between technologists, clinicians, and ethicists is crucial for harnessing AI's potential while safeguarding against risks in healthcare settings. [Extracted from the article]

Aims: There is limited real‐world data on cyclosporin A (CsA)‐induced liver injury (CILI). This study aims to investigate the incidence, clinical classification and risk factors of CILI, thereby providing evidence to inform the treatment of CILI. Methods: Inpatients receiving haematopoietic stem cell transplantation (HSCT) and treated with CsA were included. Patient information was collected to assess suspicious CILI by the Roussel Uclaf causality assessment method (RUCAM) scale. We evaluated the pattern and severity of CILI. The independent risk factors of CILI were identified by multivariable logistic regression. Results: A total of 216 allogeneic HSCT (allo‐HSCT) recipients were included in this study. The incidence of CILI was 15.3% (95% confidence interval [CI]: 10.4%–20.1%). Among these cases, 84.8% displayed a hepatocellular pattern, and 90.9% of CILI was of mild severity. Baseline alanine aminotransferase (ALT) level (OR = 1.030, 95% CI: 1.008–1.053, P =.008) and trough concentration level of CsA (OR = 1.007, 95% CI: 1.002–1.012, P =.009) were identified as independent risk factors for CILI. Conclusions: The incidence of CILI in allo‐HSCT recipients is notably high. Recipients with elevated baseline ALT levels and higher exposure to CsA are more susceptible to developing CILI. [ABSTRACT FROM AUTHOR]

Aims: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. Methods: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose‐adjusted plasma concentrations. Results: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P =.003). The dose‐adjusted plasma concentrations were 69% lower in the comedication group (P =.001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P =.037) indicating therapeutically insufficient drug concentrations. Conclusion: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole. [ABSTRACT FROM AUTHOR]

Background: Mavacamten is a first-in-class cardiac myosin inhibitor approved by the US Food and Drug Administration (FDA) for symptomatic obstructive hypertrophic cardiomyopathy (HCM). This pharmacovigilance study aimed to assess mavacamten-related adverse drug reactions (ADRs) in the real world as reported in the FDA Adverse Event Reporting System (FAERS). Methods: We conducted disproportionality analyses with four signal detection algorithms—reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker to identify mavacamten-related ADRs. Results: Out of 4,500,131 reports from the FAERS database, 1004 mavacamten-related ADRs were identified from 1 January 2022 to 30 September 2023. A total of 26 significant disproportionality preferred terms (PTs) conforming to the four signal detection algorithms were noted. Some of the statistically significant cardiac ADRs at PT level include decreased ejection fraction (EF) [ROR 33.60 (95% confidence interval, CI 21.79–51.82), PRR 32.86 (χ2 615.96), information component (IC) 5.03, IC025 4.61, empirical Bayesian geometric mean (EBGM) 32.77, EBGM05 21.25], cardiac failure [ROR 9.39 (95% CI 6.49–13.60), PRR 9.13 (χ2 202.42), IC 3.19, IC025 2.83, EBGM 9.12, EBGM05 6.30], and atrial fibrillation [ROR 16.63 (95% CI 12.72–21.75), PRR 15.66 (χ2 769.93), IC 3.97, IC025 3.71, EBGM 15.64, EBGM05 11.96]. Conclusions: The results of our study were consistent with the safety data of clinical trials, including reduced ejection fraction, atrial fibrillation, dyspnea, and syncope. We also found potential new and unexpected ADR signals, such as urinary tract infection, gout, and peripheral edema. [ABSTRACT FROM AUTHOR]

Distal renal tubular acidosis (dRTA) is characterized by a primary defect in proton secretion by α-intercalated cells of the collecting duct, leading to impaired urine acidification and resulting in metabolic acidosis, hypokalemia, and hypercalciuria. Inherited forms of dRTA are currently associated with variants in five genes (SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72), each being associated with specific extra-renal manifestations. Acquired forms can result from autoimmune diseases or drug side effects. Classical complications include nephrolithiasis, nephrocalcinosis, reduced glomerular filtration rate (GFR), bone demineralization, and growth failure. Treatment focuses on correcting the acid–base imbalance through alkali supplementation (potassium, sodium, or magnesium bicarbonate or citrate) to reduce renal disease progression and promote normal growth and mineralization. Traditional treatments (alkali and potassium supplementation) often suffer from poor adherence due to frequent day and night administrations, gastrointestinal discomfort, and unpleasant taste. A novel investigational drug, ADV7103, which contains potassium citrate and potassium bicarbonate in an extended-release formulation, has recently been approved by the European Medicine Agency (EMA) for dRTA. Recent studies support its use as a first-line treatment, given its efficacy and safety profile. [ABSTRACT FROM AUTHOR]

Treatment with immune checkpoint inhibitors for cancer is associated with a high prevalence of multiple immune-related toxicities. Immune-related adverse events (irAEs) can occur anytime during treatment and up to 3 months after treatment. This article discusses checkpoint inhibitor therapy and describes the implementation of a patient education program focused on recognizing immunotherapy irAEs and their toxicities. [ABSTRACT FROM AUTHOR]

Approximately one-third of Americans use healthcare approaches including herbs and botanicals, such as St. John's wort (SJW), to improve overall well-being, gain control over their health, and manage the adverse reactions of conventional therapies. This article examines the use of SJW in cancer care, discussing its pharmacokinetics, toxicity, and potential interactions with cancer treatments while emphasizing the importance of patient education and collaboration between oncology nurses and pharmacists to ensure safe and effective care. [ABSTRACT FROM AUTHOR]

Over the last 13 years, the use of immune checkpoint inhibitor (ICI) therapy has grown remarkably, owing to their unprecedented anti-tumor efficacy in certain tumor groups. With increased use of ICIs, we are seeing immune-related adverse events (irAEs) more frequently. Renal irAEs, such as ICI-associated acute kidney injury (ICI-AKI), are reported in 2%–5% of patients treated with ICIs, with acute tubulointerstitial nephritis (ATIN) as the most common histopathologic lesion, though various forms of glomerulonephritis have also been reported. Modifiable risk factors for ICI-AKI include concurrent use of ATIN-associated drugs, like proton pump inhibitors, non-steroidal anti-inflammatory drugs and antibiotics, and dual ICI therapy with both Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 and its ligand (PD1/PDL-1) blockade. Kidney biopsies remain the diagnostic modality of choice, though several promising non-invasive biomarkers, which have not yet been broadly clinically validated have emerged. The treatment of ICI-AKI involves holding ICIs, discontinuation of ATIN-associated drugs and initiation of immunosuppression with corticosteroids as first-line therapy. With prompt treatment initiation, most patients achieve full or partial renal recovery, allowing for re-challenge with ICI. However, a subset of patients will require additional steroid-sparing therapies for corticosteroid-dependent or refractory ICI-AKI. Here we review developments in our understanding of the pathophysiology of ICI-AKI, the approach to diagnosis (with a focus on the emergence of novel diagnostic tools), prognostic factors and the current evidence for establishing treatment standards for ICI-AKI. As the evidence base remains largely retrospective, we identify questions that would benefit from future prospective studies in the diagnosis, management and prognostication of ICI-AKI. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAEs. The study prospectively included 43 patients with metastatic disease scheduled for anti-PD-1/ L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta, and IL-17A were measured prior to ICI and during the endocrine-irAEs. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAEs (P = 0.004). In the irAE group, median pre-ICI CXCL10 and baseline thyroid stimulating hormone (TSH) levels were significantly higher, baseline total testosterone level in men was lower than in the non-irAE group (P < 0.05), whereas IL-1beta and IL-17A levels did not differ (P > 0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (P > 0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r = 0.706, P = 0.01) and negatively with baseline total testosterone level of men (r = 0.509, P = 0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction. [ABSTRACT FROM AUTHOR]

A growing body of clinical and experimental evidence indicates that immune checkpoint blockade enhances patient susceptibility to hypersensitivity reactions to co-administered medications. In this study, we utilized an in vitro T-cell priming assay to demonstrate one of the mechanistic hypotheses on how this occurs; through lowering of the threshold in patients to elicit aberrant T-cell responses. We outline the dependency of de novo T-cell priming responses to drug-associated antigens on dose at initial exposure. Findings support the aforementioned hypothesis and offer an experimental representation of fundamental parameters at play in hypersensitivity reactions to low molecular weight compounds. [ABSTRACT FROM AUTHOR]

Solid organ transplantation (SOT) is the gold standard of therapy for individuals with end‐organ dysfunction. Improved survival outcomes after SOT can help adolescent and young adult (AYA) recipients lead long and healthy life. However, successful SOT during adolescence and young adulthood is often complicated by the innate developmental challenges of this age group. The psychosocial tasks of adolescence include identity development, autonomous decision‐making, establishing social networks, educational and vocational preparation, and navigating romantic relationships. These goals may be amplified or delayed for pediatric SOT recipients. Adolescence is also marked by rapid physical changes in linear growth and the development of secondary sexual characteristics. Yet AYA may experience physical and pubertal delays related to transplantation, as well as exaggerated body image dissatisfaction due to medication side effects. Strict adherence to medication and post‐transplant regimens may interfere with adolescents' desire for normalcy and fitting in with peers. Healthcare providers should be aware that AYA value education and self‐empowerment in transplant care. Transplant success needs to be defined by both medical and psychosocial outcomes, particularly when it relates to the vulnerable AYA population. Fortunately, investment from the patient, family, and care team can aid in transplant recovery and success. This article will identify the developmental challenges faced by AYA undergoing solid organ transplantation as well as strategies to engage positive outcomes. [ABSTRACT FROM AUTHOR]

Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose–effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD. [ABSTRACT FROM AUTHOR]

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the most severe cutaneous adverse reactions that are typically drug-induced in adults. Both SJS and TEN have high morbidity and mortality rates. SJS/TEN imposes clinical challenges for physicians managing patients suffering from this condition, both because it is rare and because it is a rapidly progressing systemic disease with severe cutaneous, mucosal, and systemic manifestations. Although many cases of SJS/TEN have been reported in the literature, there is no consensus regarding diagnostic criteria or treatment. Significant progress has been made in understanding its genetic predisposition and pathogenesis. This review is intended to provide physicians with a comprehensive but practical SJS/TEN roadmap to guide diagnosis and management. We review data on pathogenesis, reported precipitating factors, presentation, diagnosis, and management SJS/TEN focusing on what is new over the last 5 years. [ABSTRACT FROM AUTHOR]

Acute generalized exanthematous pustulosis (AGEP) is a rare, usually drug‐induced, acute pustular rash. Despite the lack of strong data supporting the effectiveness of topical or systemic corticosteroids in this drug reaction, they are widely used. More generally, there is no consensus on the diagnostic modalities and the management of patients with AGEP. We aimed to provide European expert recommendations for the diagnosis and management or patients with AGEP. Members of the ToxiTEN group of the European Reference Network (ERN)‐skin, all dermatologists and/or allergologists with expertise in drug reactions, elaborated these recommendations based on their own experience and on a review of the literature. Recommendations were separated into the following categories: professionals involved, assessment of the diagnosis of AGEP, management of the patient and allergological work‐up after the acute phase. Consensus was obtained among experts for the list of professionals involved for the diagnosis and management of AGEP, including the minimum diagnostic work‐up, the setting of management, the treatments, the modalities and the timing of allergological work‐up and follow‐up. European experts in drug allergies propose herein consensus on the diagnosis and management of patients with AGEP. A multidisciplinary approach is warranted, including dermatologists, allergologists and pharmacovigilance services. [ABSTRACT FROM AUTHOR]

Objectives: To report up to 3-year safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a postmarketing surveillance study. Methods: Patients enrolled previously completed 24 weeks of CZP in the 24-week postmarketing surveillance study. Adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes were 28-joint Disease Activity Score with erythrocyte sedimentation rate and European Alliance of Associations for Rheumatology response. Week 24–156 safety and Week 0–52 effectiveness data are reported here. Results: A total of 781 patients were enrolled, with 735 and 376 patients evaluated for safety and effectiveness, respectively. Within the safety set, 17.8% (131/735) of patients reported ADRs; 9.4% (69/735) reported serious ADRs. Among patients with history of respiratory, thoracic, and mediastinal disorders, 38.4% (28/73) reported ADRs. The most frequent ADRs were infections and infestations (11.8%; 87/735); skin and subcutaneous tissue disorders (1.9%; 14/735); respiratory, thoracic, and mediastinal disorders (1.6%; 12/735). Mean 28-joint Disease Activity Score with erythrocyte sedimentation rate reduced from 4.6 (Week 0) to 2.8 (Week 52). At Week 52, 51.8% (161/311) of patients achieved European Alliance of Associations for Rheumatology Good response. Conclusions: The long-term safety and effectiveness of CZP in the real-world setting in Japan were consistent with previously reported data; no new safety signals were identified. [ABSTRACT FROM AUTHOR]

Objective. To characterize adverse event (AE) cases received by the US Food and Drug Administration (FDA) reportedly involving cannabinoid hemp products (CHPs). Methods. We searched the FDA Adverse Event Reporting System and Center for Food Safety and Applied Nutrition Adverse Event Reporting System for cases reported directly to the FDA from 2019–2023 involving CHPs, which are defined as products containing 1 or more of the following: cannabidiol, delta-8 tetrahydrocannabinol, and emerging cannabinoids (i.e., other intoxicating cannabinoids often synthesized from hemp-derived cannabidiol). We abstracted and summarized information on reporting trends, consumer demographics, reporter information, product information, and AEs. Results. We identified 610 AE cases reportedly involving CHPs containing 1 or more of the following: delta-8 tetrahydrocannabinol (n=355), cannabidiol (n=253), and emerging cannabinoids (n=36). Multiple trends and safety issues were identified, including an annual increase in the number of cases involving intoxicating cannabinoids since 2021, potential quality issues, and the occurrence of fatalities and pediatric exposures. Conclusions. Our findings emphasize the importance of monitoring AE cases received by the FDA involving CHPs as part of a comprehensive surveillance strategy to identify trends and safety issues with these products. (Am J Public Health. 2024;114(S8):S664–S672. https://doi.org/10.2105/AJPH.2024.307712) [ABSTRACT FROM AUTHOR]

The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments. [ABSTRACT FROM AUTHOR]

Background and Objectives: Statistical methods for signal detection of adverse drug reactions (ADRs) in electronic health records (EHRs) need information about optimal significance levels and sample sizes to achieve sufficient power. Sauzet and Cornelius proposed tests for signal detection based on the hazard functions of Weibull type distributions (WSP tests) which use the time-to-event information available in EHRs. Optimal significance levels and sample sizes for the application of the WPS tests are derived. Method: A simulation study was performed with a range of scenarios for sample size, rate of event due (ADRs), and not due to the drug and random time to ADR occurrence. Based on the area under the curve of the receiver operating characteristic graph, we obtain optimal significance levels of the different WSP tests for the implementation in a hypothesis free signal detection setting and approximate sample sizes required to reach a power of 80% or 90%. Results: The dWSP–pPWSP (combination of double WSP and power WSP) test with a significance level of 0.004 was recommended. Sample sizes needed for a power of 80% were found to start at 60 events for an ADR rate equal to the background rate of 0.1. The number of events required for a background rate of 0.05 and an ADR rate equal to a 20% increase of the background rate was 900. Conclusion: Based on this study, it is recommended to use the dWSP–pWSP test combination for signal detection with a significance level of 0.004 when the same test is applied to all adverse events not depending on rates. [ABSTRACT FROM AUTHOR]

Background: Seasonal influenza is prevented through annual vaccination, especially in children and older adults. These vaccines are annually updated based on World Health Organization recommendations and require continuous safety monitoring. Objective: We assessed the frequency and severity of adverse events within 7 days of administering GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) in Belgium, Germany, and Spain during the 2022/2023 influenza season. Methods: In this enhanced safety surveillance study, adults who received GSK's IIV4 and parents/guardians/legally acceptable representatives of vaccinated children (aged 6 months–17 years) were invited to complete adverse drug reaction cards reporting adverse events within 7 days post-vaccination. Results: In total, 1332 participants (53.6% female) received at least one dose of GSK's IIV4, including 43 children who received two doses. Overall, 97.8% of adverse drug reaction cards were completed and returned in the study. All participants in Belgium were adults, while 54.7% and 7.4% in Spain and Germany, respectively, were pediatric participants aged 6 months–17 years. After Dose 1, across all age groups, 49.8% of participants reported at least one adverse event. The most common adverse events (cumulative frequency >5%) following Dose 1 were injection-site pain (37.6%), fatigue (15.0%), headache (13.2%), injection-site swelling (9.3%), myalgia (7.6%), and injection-site erythema (7.4%). Across all countries, adverse events were most common in adults aged 18–65 years (59.7%), followed by those aged 3–17 years (47.0%), >65 years (35.7%), and 6–35 months (23.5%). After Dose 2, 18.6% of participants reported at least one adverse event, with general disorders and administration site conditions again being the most frequent. Conclusions: Across all age and risk groups for serious disease, no serious adverse events related to GSK's IIV4 were reported within 7 days post-vaccination. This study supports and confirms the acceptable safety profile of GSK's IIV4 across all recommended age groups. Clinical Trial Registration: ClinicalTrials.gov number: not applicable. [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]

Background: Pimitespib (TAS‐116), a first‐in‐class, oral, selective heat‐shock protein 90 inhibitor, is approved as fourth‐line treatment for gastrointestinal stromal tumors in Japan. This phase 1 study evaluated the cardiac safety of pimitespib. Methods: In this open‐label, nonrandomized, multicenter study, Japanese patients (aged ≥20 years) with refractory, advanced solid tumors received placebo on day −1, then pimitespib 160 mg daily on days 1–5 of the cardiac safety evaluation period. Electrocardiograms were conducted at baseline, and on days −2, −1, 1, and 5; and blood samples were collected on days 1 and 5. Patients then received once‐daily pimitespib for 5 days every 3 weeks. The primary end point was the time‐matched difference in QT interval corrected for heart rate using the Fridericia correction (QTcF) between pimitespib and placebo. Pharmacokinetics, safety, and preliminary efficacy were also assessed. Results: Of the 22 patients in the cardiac safety‐evaluable population, no clinically relevant QTc prolongation was observed; the upper bound of the one‐sided 95% confidence interval for the time‐matched difference in change from baseline in QTcF was <20 msec at all time points on days 1 and 5. Pimitespib pharmacokinetic parameters were consistent with previous data, and the time‐matched difference in change from baseline in QTcF showed no marked increase as plasma concentrations increased. The safety profile was acceptable; 40% of patients experienced grade 3 or greater adverse drug reactions, mostly diarrhea (20%). The median progression‐free survival was 3.1 months. Conclusions: In Japanese patients with refractory, advanced solid tumors, pimitespib was not associated with clinically relevant QTc prolongation, and there were no cardiovascular safety concerns. Plain Language Summary: Pimitespib is a new anticancer drug that is being used to treat cancer in the stomach or intestines (gastrointestinal stromal tumors).This study demonstrated that pimitespib had no marked effect on heart rhythm or negative effects on the heart or blood vessels and had promising anticancer effects in Japanese patients with advanced solid tumors who were unable to tolerate or benefit from standard treatment. [ABSTRACT FROM AUTHOR]

Purpose: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI). Methods: We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024. Results: A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms. Conclusion: Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis. [ABSTRACT FROM AUTHOR]

Purpose: To comprehensively evaluate and compare all the available reference guides for the safe use of drugs during pregnancy, with the goal of determining the scientificity and reliability of these reference guides. Methods: We searched PubMed, EMbase, CNKI, Wanfang Database, and VIP database to comprehensively identify the available reference guides. Moreover, we selected 103 drugs based on relevant literatures, and compared the recommendations of each drug from different reference guides. Results: A total of 14 available reference guides were identified. However, none of these reference guides assessed the risk of bias of original studies or the quality of current evidence. Seven reference guides adopted expert consensus method to formulate pregnancy recommendations, while the rest reference guides did not report the formation method. Moreover, 77.7% of the selected drugs had inconsistent recommendations among different reference guides. In addition, the referenced human and animal studies for the same drug differed among different reference guides. Conclusion: Our results indicate that current reference guides for the safe use of drugs during pregnancy are less scientific and reliable, and there are considerable discrepancies in recommendations from different reference guides concerning drug use during pregnancy. The reasons for the discrepancies in recommendations include ① the literature search in most reference guides was not comprehensive, ② none of the available reference guides assessed the risk of bias of original studies or the quality of current evidence, and ③ the method adopted by current reference guides to formulate recommendations had obvious subjectivity and lacked of scientificity. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (mAbs) are pivotal in treating various diseases, including cancers and autoimmune disorders. Despite their therapeutic benefits, mAb therapy has been associated with neurological toxicity. Objectives: This study aimed to assess the occurrence of neuronal toxicity associated with mAbs, utilizing data from the FDA Adverse Event Reporting System (FAERS) safety database. The study also sought to delineate the medical characteristics of the reported cases. Methods: A comprehensive analysis of neurological adverse events reported in the FAERS database was conducted, employing computational methodologies such as proportional relative risk (PRR), information component (IC025), and chi-square (χ2). Individual case safety reports (ICSRs) pertaining to neurological disorders linked to mAbs from the date of first global marketing authorization until June 30, 2023, were meticulously examined. Results: The FAERS safety database contains 79,022 ICSRs linking mAbs to nervous system disorders. Rituximab, bevacizumab, denosumab, nivolumab, and trastuzumab were frequently cited. Reported adverse events include headache, peripheral neuropathy, dizziness, and cerebrovascular accident. Most ICSRs (85.81%) were serious, mainly affecting females (57.04%) with a 14.09% fatality rate. Panitumumab, atezolizumab, bevacizumab, and trastuzumab showed strong drug-event associations. Signal disproportionate reporting (SDR) analysis flagged myasthenia gravis, peripheral neuropathy, and neurotoxicity across multiple mAbs, suggesting potential signals. Conclusions: Interdisciplinary collaboration between oncologists and neurologists is crucial for safe mAb use. Our study enhances understanding of mAb neurological safety. Disproportionality signal analysis provides valuable evidence for risk mitigation. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the potential association between suicidality and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), as well as other medications used for obesity and diabetes, using comprehensive global data. Materials and Methods: This study utilized the World Health Organization's pharmacovigilance database, encompassing adverse drug reaction reports from 1967 to 2023, from 170 countries (total reports, N = 131 255 418). We present the reported odds ratios (RORs) with 95% confidence intervals (CIs) and information component (IC) with IC025 regarding the association between GLP‐1RA use and suicidality. Results: Although reports of GLP‐1RA‐associated suicidality increased gradually from 2005 to 2023 (n = 332), no evidence of an association was observed (ROR 0.15 [95% CI 0.13 to 0.16]; IC −2.77 [IC025 −2.95]). The lack of evidence of an association persisted regardless of whether GLP‐1RAs were used for diabetes treatment (ROR 0.13 [95% CI 0.11 to 0.14]; IC −2.95 [IC025 −3.14]) or obesity treatment (ROR 0.44 [95% CI 0.34 to 0.58]; IC −1.16 [IC025 −1.62]). However, an association was found between suicidality and other diabetes medications excluding GLP‐1RAs (ROR 1.13 [95% CI 1.10 to 1.15]; IC 0.17 [IC025 0.13]). Similarly, the potential association with suicidality was observed in medications used to treat obesity excluding GLP‐1RAs (ROR 1.08 [95% CI 1.01 to 1.14]; IC 0.10 [IC025 0.01]). Conclusions: The suspected association between GLP‐1RA use and suicidality, as raised by the European Medicines Agency, was not found in our global analysis. This indicates that the sporadic reports of GLP‐1RA‐associated suicidality are likely influenced by factors such as comorbidities present in the GLP‐1RA user population. [ABSTRACT FROM AUTHOR]

Background: Substance use carries a wide range of negative consequences, impacting both the individual using the substances and others. In recent years, there have been multiple efforts to assess the harm caused by drugs and to rank them, with each taking a distinctive approach to the matter. Objectives: This study seeks to introduce a new model for assessing the harm index and ranking of drugs. Methods: This prospective study involved the evaluation of 277 male drug users, assessing substance use harm on four separate occasions throughout the span of 1 year. Various aspects of harm were quantified through the utilization of the Duke Health Profile (DUKE) and the Addiction Severity Index (ASI) questionnaire. The pharmaceutical properties of each drug were incorporated into the study. The relationship between the combined variables in a mixed statistical model was determined at a significance level of.05 using the Rsoftware. This procedure facilitated the establishment of models and the definition of harm index ranges for each substance. Result: The results indicated that heroin had the highest harm index at 71.2 (95% CI69.6–72.8), while pure methadone scored the lowest at 36.5 (95% CI31.7–41.7), along with methadone combined with methamphetamine, which scored 35 (95% CI33–37.1). Conclusion: The variables utilized in this study can help estimate the approximate harm index range for both traditional and novel substances. Furthermore, the harm model designed in this study has the capability to predict the extent of harm to a drug user. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Doxorubicin (Dox) is a very useful drug in these patients, however, one of the main adverse effects caused by the use of Dox is cardiotoxicity (CT). Protein-calorie malnutrition (PCM) is a factor that, among others, can influence the development of CT due to Dox. The aim of our study was to associate PCM as a risk factor for CT induced by Dox in Mexican children with ALL. We included 89 children with ALL who were treated with Dox, from October 2018 to July 2023, and of whom 14 developed some type of CT, 15 were underweight and 3 were overweight. The analysis of the association risk of CT due to PCM shows a statistically significant association of risk of developing CT due to PCM. On the other hand, healthy weight was associated with protection for developing CT due to Dox use. Of the total number of girls who presented CT, all had systolic dysfunction, while 6 of them also had diastolic dysfunction. On the other hand, of the total number of boys who presented CT, all of them had systolic dysfunction and only one of them also had diastolic dysfunction. These results show that in patients in which Dox is being administered, special attention is suggested for girls with PCM, since systolic failure is a precursor and occurs before diastolic failure in girls with PCM. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) non-surgical procedures are increasingly popular, with approximately 5.6 million performed annually by plastic surgeons worldwide. These treatments effectively address signs of aging in the forehead and nasofrontal areas but come with risks such as bruising, swelling, infections, inflammation, granulomas, skin necrosis, and vascular obstructions. The nose, forehead, and glabella are particularly high-risk areas for visual changes and embolic complications. The nasofrontal region's vascular network is supplied by branches from both the external and internal carotid arteries. The external carotid artery includes the lateral nasal, columellar, and angular arteries, while the frontal branch of the superficial temporal artery supplies the temporal and lateral frontal areas. The internal carotid system, via the ophthalmic artery, includes the supratrochlear, supraorbital, and dorsal nasal arteries, supplying the central and middle forehead and upper nasal dorsum. These networks form a robust vascular arcade. Patients with vascular complications from facial injections often present with a reticulated skin pattern, hematoma, ecchymosis, tenderness, pain, pressure, and sometimes scabs or pustules. Specific skin patterns are associated with vascular complications in defined facial areas. A structured treatment protocol using targeted ultrasound-guided hyaluronidase injections effectively manages these complications, emphasizing a detailed understanding of vascular anatomy and precise diagnostic tools. [ABSTRACT FROM AUTHOR]

Childhood is a significant period that affects a person’s health throughout their whole life. Children deserve to receive quality medical care. It is also the responsibility of parents to be aware of treatment methods and to ensure that their children receive the best medical and pharmaceutical care. An essential point of drug therapy in children is the administration of drugs without a doctor’s prescription. The aim of this article is to research the importance of pharmaceutical care provided in counseling parents in the purchase of over-the-counter (OTC) drugs. Material and methods. A review of the scientific literature was performed in the databases of PubMed and Google Scholar. The study was carried out in the period from 01.02.2024 to 31.03.2024 using key words: “pharmaceutical care”, “children”, “OTC drugs”, “adverse drug reactions”. Results. OTC drugs are widely available, allowing patients to self-medicate and also parents to give them to their children. Children get sick much more often and have an elevated body temperature compared to adults. OTC drugs are considered safe for use in pediatric patients when used according to the instructions on their label. Non-prescription drugs also include analgesics such as Aspirin and Paracetamol, some of the medicines for coughs, hay fever, etc. Conclusion. The pharmacist provides information about medicines, their correct use and the possibility of adverse drug reactions and/or interactions with food and other medicines and is also a responsible participant in the provision of primary health care. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, there was a marked increase in alcohol and drug-induced deaths. In the US, there was a rapid increase in the rate of alcohol- and drug-induced deaths within the first year of the COVID-19 pandemic compared to pre-pandemic years. This study examines mortality data within Hawai'i to assess both alcohol and drug-induced mortality during the pandemic compared to the nation overall. Data from the Centers for Disease Control and Prevention Underlying Cause of Death database were used to compare numbers and rates of alcohol-induced, drug-induced, and all-cause deaths among individuals aged 15 years or older between 2018 and 2021. The percentage of alcohol-induced and drug-induced deaths in the US and Hawai'i increased annually in 2018, 2019, 2020, and 2021. Unlike the US, in Hawai'i between 2020 and 2021 the age-adjusted rate of drug-induced deaths per 100 000 people decreased from 20.6 to 18.6. Overall, this study found that alcohol-related deaths in Hawai'i increased similarly to those in the US during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Objective: Over time, most patients with schizophrenia wish to reduce or discontinue their antipsychotic medication treatment. In Denmark, a specialized government-funded outpatient clinic was established to offer guided antipsychotic dose reduction. This study aimed to provide data on motivations for and previous experiences with antipsychotic tapering among patients attending the clinic. Methods: Patients completed an open-ended survey on their motivations for discontinuing or tapering antipsychotic medication and recorded their expectations about these outcomes. They also provided information on previous experiences with discontinuing medication and their level of symptoms, functioning, and side effects. Results: The survey was completed by 76 (86%) of 88 patients. The main motivations for discontinuing antipsychotics were adverse effects (71%) and uncertainty about the necessity of taking antipsychotics (29%). Other factors included concerns about long-term effects, disagreeing with the diagnosis, experiencing an insufficient effect, and feeling stigmatized by taking medication. Previous experience with discontinuation of antipsychotics was reported by 42 patients, of whom 23 reported relapse as the outcome. Most patients believed they could succeed in dose reduction (N=73 of 75, 97%) or discontinuation (N=62 of 75, 83%). Conclusions: Motivational factors reported for professionally guided antipsychotic dose reduction align with previous studies examining patients choosing to discontinue these medications. Despite reports of relapse during prior discontinuation attempts, most patients still reported motivation for and belief in successful dose reduction or discontinuation. An understanding of patients' motivations and beliefs is paramount to an optimal treatment alliance. Offering guided dose reduction may reduce sudden and unsupported discontinuation of antipsychotics. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Care Excellence (NICE) has updated its guidelines on preventing cardiovascular disease, particularly focusing on lipid management. The new guidance expands the range of patients eligible for lipid-lowering therapy based on lifetime risk of cardiovascular disease. While statins are the first-line treatment, the guidance emphasizes patient-centered care and individualized treatment, with lifestyle interventions recommended alongside medication. The update may lead to increased workload for GPs but aims to reduce future cardiovascular events and improve population health. [Extracted from the article]

Background: People with gender dysphoria are treated with hormone therapy for gender reassignment. The indication of this therapy was initially for the opposite sex, and information on potential adverse drug reaction (ADR) is lacking. Objective: To describe ADR associated with gender transition medication in transgender individuals reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data from the FAERS database up to June 2023 were examined, focusing on reports of gender transition medication use in the context of gender dysphoria. The ADRs were categorized using the Medical Dictionary for Regulatory Activities at both Preferred Term and System Organ Class (SOC) levels. Descriptive statistics summarized report counts, medication types, indications, and ADR severity. Results: For individuals assigned female at birth undergoing gender transition to male (transgender men), 82 reports (230 ADRs) were analyzed, with an average age of 29.5 years. Transgender hormonal therapy was cited in 72% of reports, predominantly from the United States (67.1%). A striking 88% were categorized as serious ADRs, primarily SOC injury, poisoning, and procedural complications (26.5%), followed by psychiatric disorders (14.8%) and nervous system disorders (12.2%). Among those assigned sex male at birth transitioning to female (transgender women) (81 reports, 237 ADRs), mean age was 33.3 years, with 58% indicating use for gender dysphoria. A significant proportion (53.6%) were serious ADRs, primarily SOC: injury, poisoning, and procedural complications (26.6%). Conclusions and Relevance: The FAERS data reveal significant ADRs in transgender individuals using hormone therapy, sometimes unintended for their recipient gender. Population-level studies are crucial to enhance transgender health care. Spontaneous surveillance databases like FAERS illuminate off-label ADRs, urging health care providers to approach hormone therapies with informed caution. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α. [ABSTRACT FROM AUTHOR]

Background: We explored the efficacy and safety of esketamine combined with propofol for conscious sedation in painless colonoscopy. Methods: A total of 195 patients who underwent painless colonoscopy surgery were randomly divided into three groups: the propofol deep sedation group (group DS), the sufentanil combined with propofol for conscious sedation (group CS1) and the esketamine combined with propofol for conscious sedation (group CS2). The primary outcomes of this study included the incidence of hypoxemia, hypotension, hypertension, and bradycardia and excellent and good rates of anaesthesia during colonoscopy. The secondary outcomes included perioperative changes in vital signs (MAP, HR, and SpO2), anaesthesia induction time, dischargeable time, patient and endoscopist satisfaction scores, and incidence of postoperative nausea and vomiting (PONV), drowsiness, dizziness, propofol injection pain, assisted ventilation and vasoactive medications. Results: The incidence of intraoperative hypoxemia in the DS group was significantly greater than that in the CS1 and CS2 groups (χ2 = 7.081, P = 0.029). The incidence of hypotension in the CS2 group was significantly lower than that in the DS and CS1 groups (χ2 = 16.278, P < 0.001). The risk of hypoxemia was 5.727 times higher in Group DS than in Group CS2 (OR 5.727; 95%CI 1.203–27.273), and the risk of hypotension was 9.864 times higher in Group DS than in Group CS2 (OR 9.864; 95%CI 2.770–35.120). The risk of hypotension in Group CS1 was 5.167 times that in Group CS2 (OR 5.167; 95%CI 1.396–19.117). The incidence of propofol injection pain, assisted ventilation, ephedrine usage and drowsiness in the DS group was significantly greater than that in the CS1 and CS2 groups (χ2 = 57.618, P < 0.001; χ2 = 9.544, P = 0.008; χ2 = 14.820, P = 0.001; χ2 = 37.257, P < 0.001). The incidence of dizziness during recovery in the CS1 group was significantly greater than that in the DS and CS2 groups (χ2 = 6.594, P = 0.037). The dischargeable time in the DS group was significantly greater than that in the CS1 and CS2 groups (F = 53.039, P < 0.001). The satisfaction scores of the endoscopist and patients in the DS group were significantly lower than those in the CS1 and CS2 groups (F = 17.390, P < 0.001; F = 19.282; P < 0.001). Conclusions: In conclusion, esketamine combined with propofol for conscious sedation can be safely and effectively used for painless colonoscopy and has fewer complications.It is recommended for painless colonoscopy. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016–2019) was conducted to generate real‐world evidence.Treatment‐naïve (TN) and treatment‐experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient‐reported outcomes, using the HIV Symptom Index (HIV‐SI), 36‐Item Short Form Health Survey (SF‐36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires.The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/μL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti‐HIV Drugs) 5‐year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple‐tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV‐SI and SF‐36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE.Real‐world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF‐based ART. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted that TACE in conjunction with Lenvatinib (TACE-L) offers a promising adjunct therapy for advanced HCC patients, outperforming TACE plus Sorafenib (TACE-S). However, there has been a lack of research comparing these two regimens for intermediate HCC. Aims: This study aims to address the research gap by evaluating the efficacy of TACE-L versus TACE-S in intermediate HCC patients. Methods: A retrospective analysis was conducted on a cohort of consecutive intermediate HCC patients who received either TACE-L or TACE-S from November 2018 to December 2022. Portal vein width was assessed using abdominal NMRI or Doppler ultrasonography, and inflammatory markers were derived from routine blood counts. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse drug reactions (ADRs). Results: The study included 117 patients, with 56 in the TACE-S group and 61 in the TACE-L group. The TACE-S group demonstrated superior OS (HR = 1.704, 95% CI: 1.012–2.870, p = 0.045) compared to the TACE-L group. No significant difference was observed in PFS (HR:1.512, 95% CI: 0.988–2.313, p = 0.057) between the two groups. Subgroup analyses revealed that male patients, those with cirrhosis, and those with more than four tumors had better OS and PFS in the TACE-S group than in the TACE-L group. Inflammatory markers were comparable between the groups. The TACE-S group experienced a higher incidence of palmar-plantar erythrodysesthesia syndrome (PPE) (14/56 [25%] vs. 5/61 [8.1%], p = 0.014) but a lower incidence of hypertension (3/56 [5.3%] vs. 11/61 [18%], p = 0.035) compared to the TACE-L group. Conclusions: In patients with intermediate HCC, TACE-S was found to be more effective in terms of OS than TACE-L. No significant disparity was noted in PFS between the two treatment groups. [ABSTRACT FROM AUTHOR]

Background: Ciprofol was approved for use in intensive care unit (ICU) patients requiring sedation during mechanical ventilation in July 2022. A pooled post-hoc analysis of phase 2 and phase 3 trials was conducted primarily to explore hypotension-free outcome in ICU patients who required mechanical ventilation and achieved the target light sedation goal at an early stage after being sedated with ciprofol or propofol. Methods: All eligible ICU patients who were expected to require sedation for 6–24 h were randomly assigned in a 2:1 ratio to either a ciprofol or propofol group. Ciprofol or propofol was initially infused at loading doses of 0.5 or 1.0 mg/kg followed by maintenance doses of 0.3 or 1.5 mg/kg/h. Ciprofol or propofol dosages were adjusted up or down at rates of 0.05–0.10 mg/kg/h or 0.25–0.50 mg/kg/h, respectively, to achieve the target light sedation (a Richmond Agitation-Sedation Scale of -2 to + 1). The primary post-hoc outcome was the hypotension-free rate in patients who had achieved the target sedation goal after 30-min administration of ciprofol or propofol. Results: In total, 174 patients were enrolled for pooled post-hoc analysis, of whom 116 and 58 were assigned to the ciprofol and propofol groups, respectively. The hypotension-free rate was significantly higher in patients who achieved the target sedation goal after 30-min administration of ciprofol (93.0% vs. 81.0%, P = 0.018), and especially in the subgroups of males and patients aged < 65 years. Multivariable analysis revealed that ciprofol treatment, a younger age and lower baseline body mass index were independent favorable predictors for a higher hypotension-free rate in patients who achieved the target sedation goal after 30-min of drug administration. Moreover, hypotension-free patients who reached the target sedation level after 30 min had a more favorable short-term prognosis including a lower incidence of drug-related treatment-emergent adverse events, shorter time to extubation and fewer dose adjustments of ciprofol or propofol (all P < 0.05). Conclusion: ICU patients undergoing mechanical ventilation and sedated with ciprofol had significantly lower rate of hypotension during the early phase of achieving light sedation during a 6–24 h period, leading to a more favorable short-term prognosis (within 24 h). Trial registration: Phase 2 trial (clinicaltrials.gov, NCT04147416. Registered November 1, 2019, https://classic.clinicaltrials.gov/ct2/show/NCT04147416) and phase 3 trial (clinicaltrials.gov, NCT04620031. Registered November 6, 2020, https://classic.clinicaltrials.gov/ct2/show/NCT04620031). [ABSTRACT FROM AUTHOR]

Background: Pregnant women are significantly underrepresented in clinical trials, yet most of them take medication during pregnancy despite the limited safety data. The objective of this study was to characterize medication use during pregnancy and apply propensity score matching method at scale on patient records to accelerate and prioritize the drug effect signal detection associated with the risk of preterm birth and other adverse pregnancy outcomes. Methods: This was a retrospective study on continuously enrolled women who delivered live births between 2013/01/01 and 2022/12/31 (n = 365,075) at Providence St. Joseph Health. Our exposures of interest were all outpatient medications prescribed during pregnancy. We limited our analyses to medication that met the minimal sample size (n = 600). The primary outcome of interest was preterm birth. Secondary outcomes of interest were small for gestational age and low birth weight. We used propensity score matching at scale to evaluate the risk of these adverse pregnancy outcomes associated with drug exposure after adjusting for demographics, pregnancy characteristics, and comorbidities. Results: The total medication prescription rate increased from 58.5 to 75.3% (P < 0.0001) from 2013 to 2022. The prevalence rate of preterm birth was 7.7%. One hundred seventy-five out of 1329 prenatally prescribed outpatient medications met the minimum sample size. We identified 58 medications statistically significantly associated with the risk of preterm birth (P ≤ 0.1; decreased: 12, increased: 46). Conclusions: Most pregnant women are prescribed medication during pregnancy. This highlights the need to utilize existing real-world data to enhance our knowledge of the safety of medications in pregnancy. We narrowed down from 1329 to 58 medications that showed statistically significant association with the risk of preterm birth even after addressing numerous covariates through propensity score matching. This data-driven approach demonstrated that multiple testable hypotheses in pregnancy pharmacology can be prioritized at scale and lays the foundation for application in other pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Despite their dangerous side effects, opioid drugs remain a standard of care for moderate to severe pain with few alternatives. Strategies to maintain the analgesic effects of opioids while minimizing the associated risks are needed. Pre-clinical studies have shown using a dopamine 3 receptor (D3R) agonist as an adjuvant to morphine provides superior analgesia against painful stimuli compared to morphine alone. Our objective was to test if adjunct treatment with a D3R agonist can lead to a reduction in opioid use while maintaining effective analgesia. Patients and methods: This study was set up as a double-blinded, placebocontrolled randomized trial. Enrollment included acute renal colic patients presenting to the emergency department, from which patients were randomized to either the "control" or "study arm". The control group received standard treatment of care (morphine, 0.1 mg/kg; i.v.) and an oral placebo pill. The experimental group received half-dosed morphine and oral pramipexole pill (0.25 mg). Pain measurements including a numerical pain scale and visual analog scale were collected from enrollees at baseline and every subsequent 15 min. Results: A total of 19 patients completed the study, 10 in the experimental arm and 9 in the control arm. During the study period, effective analgesia (50% decrease from baseline) was achieved in 80% of patients in the experimental arm vs. 33.3% in the control arm. Conclusion: Our pilot clinical trial demonstrated that D3R recruitment can serve as an effective adjuvant to low-dose morphine for control of renal colic pain and potentially other acute pain conditions. [ABSTRACT FROM AUTHOR]

Introduction: Antipsychotic psychopharmacotherapy is associated with the risk of drug-induced liver injury (DILI). However, understanding specific risk factors remains challenging due to limited data. This study investigates the relationship between receptor binding affinities and occupancies of antipsychotics and their associated hepatotoxic risks. Methods: A disproportionality analysis with calculation of the Reporting Odds Ratio (ROR) and the Information Component (IC) was conducted using data from the FDA Adverse Event Reporting System (FAERS) to identify signals related to the Standardised MedDRA Query "drug-related hepatic disorders", which served as a proxy for drug-induced hepatotoxicity. This was followed by a pharmacoepidemiologic-pharmacodynamic approach to investigate the relationship between the ROR and substance-related receptor binding affinities and occupancy, which was estimated based on in vitro receptor-binding profiles. Results: Significant signals were identified for several antipsychotics, including chlorpromazine, loxapine, olanzapine, and quetiapine, with chlorpromazine and loxapine showing the highest RORs for DILI. Gender-specific analysis revealed a higher frequency of signals in female patients. Statistically significant negative correlations were identified between the ROR for drug-related hepatic disorders and the affinity for serotonin receptor 5-HT1A (r (17) = -0.68, p = 0.0012), while a positive correlation was observed for cholinergic receptors (r (17) = 0.46, p = 0.048). No significant correlations were found related to other receptors or drug properties. Conclusion: Our findings suggest that the serotonin and probably the cholinergic system may play a role in the development of DILI related to antipsychotic medications. The identification of antipsychotics with a higher association with DILI, such as chlorpromazine, underscores the need for careful monitoring in clinical practice. However, our findings need further longitudinal studies to confirm causality. A better understanding of the associations may inform clinical decision-making, particularly in patients with an increased susceptibility to liver damage. [ABSTRACT FROM AUTHOR]

Background: Fluoroquinolones are broad-spectrum antibiotics with significant antimicrobial activity. Despite their therapeutic benefits, they are associated with a range of adverse drug reactions (ADRs), particularly those affecting the central nervous system (CNS). This study aimed to analyze the psychiatric ADRs linked to fluoroquinolones using data from the FDA Adverse Event Reporting System (FAERS) database. Methods: A retrospective pharmacovigilance study was conducted using FAERS data from Q1 2004 to Q4 2023. The data processing phase involved the FDArecommended deduplication method, and ADRs were classified according to Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed using the reporting odds ratio (ROR), and statistical significance was assessed using the Chi-square test or Fisher's exact test. Results: The study identified 84,777 reports associated with fluoroquinolones, with 359,480 Preferred Terms-annotated entries, 27,816 of these reports were psychiatric ADRs. Mood disorders were the most frequently reported, including anxiety, depression, and delirium, with some reports escalating to suicidal ideation and behaviors. The Standardized MedDRA Query classification system was used to categorize these ADRs into Depression, Suicide/self-injury, Psychosis and psychotic disorders, and Non-infectious encephalopathy/delirium. Ciprofloxacin was most frequently linked to depression and suicidal ideation, while moxifloxacin showed a robust correlation with delirium. The risk of psychiatric ADRs varied by age group, with affective disorders more prevalent in adults under 65 and psychosis and delirium in those over 65. Conclusion: Fluoroquinolones are associated with a range of psychiatric ADRs, with notable differences between the drugs in the class. The study highlights the need for caution in prescribing fluoroquinolones, particularly for patients with pre-existing mental health conditions or those in higher risk age groups. The findings also underscore the importance of considering age-specific preventive strategies when administering these antibiotics. [ABSTRACT FROM AUTHOR]

Objective: This study explores the frequency of human leukocyte antigen (HLA) genes, particularly HLA-B alleles, within the Kuwaiti population. We aim to identify alleles with known associations to adverse drug reactions (ADRs) based on existing literature. We focus on the HLA-B gene due to its well-documented associations with severe cutaneous adverse reactions and the extensive pharmacogenetic research supporting its clinical relevance. Methods: We utilized the HLA-HD tool to extract, annotate, and analyse HLA-B alleles from the exome data of 561 Kuwaiti individuals, sequenced on the Illumina HiSeq platform. HLA typing was conducted using the HLA-HD tool with a reference panel from the IPD-IMGT/HLA database. The major HLA-B pharmacogenetic markers were obtained from the HLA Adverse Drug Reaction Database, focusing on alleles with significant ADR associations in published literature. Results: The distribution of HLA-B alleles in the Kuwaiti population revealed that the most frequent alleles were HLA-B*50:01 (10.52%), HLA-B*51:01 (9.89%), HLA-B*08:01 (6.06%), HLA-B*52:01 (4.55%), HLA-B*18:01 (3.92%), and HLAB* 41:01 (3.65%). Notably, alleles HLA-B*13:01, HLA-B*13:02, HLA-B*15:02, HLA-B*15:13, HLA-B*35:02, HLA-B*35:05, HLA-B*38:01, HLA-B*40:02, HLAB* 44:03, HLA-B*51:01, HLA-B*57:01 and HLA-B*58:01 were identified with known associations to various ADRs. For example, HLA-B*51:01 was associated with clindamycin, phenobarbital, and phenytoin, and was found in 18% of individuals. Conclusion: Our study enriches the regional genetic landscape by delineating HLA-B allele variations within Kuwait and across the Arabian Peninsula. This genetic insight, along with the identification of markers previously linked to drug hypersensitivity, provides a foundation for future pharmacogenetic research and potential personalized medicine strategies in the region. [ABSTRACT FROM AUTHOR]

Immunotherapy is increasingly used in advanced non-small-cell lung cancer (NSCLC), offering a significant anti-tumor response, as well as causing rising immune-related adverse effects. The incidence of immune checkpoint inhibitorinduced myocarditis-myositis-myasthenia gravis is increasing and particularly concerning due to its high mortality rate. Prompt recognition, diagnosis, and management are crucial. A 40-year-old patient, diagnosed with stage IV nononcogene addicted lung adenocarcinoma, with nivolumab-ipilimumab-chemotherapy as first-line treatment, developed a rare myocarditis-myositis-myasthenia gravis overlap syndrome. Following the treatment, the patient presented with flu-like symptoms and chest pain and subsequently transferred to the cardiac intensive care unit. The physical examination revealed a visual acuity deficit, diplopia, ophthalmoparesis, ptosis, mydriasis, dysphagia, dyspnea, headache, nausea, dry mouth, asthenia, myalgia, and muscle weakness. Imaging and laboratory tests confirmed the triad, showing an elevation of hs-cTnI and CK and positive results for anti-SAE1 and anti-PL-7 Abs. ECG revealed ST segment elevation and RBBB. The echo showed hyperechogenicity of the inferolateral wall, pericardial detachment, and thickening. The cardiac MRI demonstrated hypokinesia, edema, subepicardial LGE, and pericardial effusion. Muscle biopsy revealed muscle fiber necrosis and regeneration with B and T lymphocytic endomysial inflammatory infiltrate and expression of MHC-I. Treatment with oral prednisone, pyridostigmine, and IV Igs was started due to poor clinical response followed by methylprednisolone. Despite stopping immunotherapy, the patient continued to benefit from it, as highlighted on subsequent reevaluation CT scans by partial disease response, and as the patient was in complete remission, we decided to resume chemotherapy by omitting immunotherapy. At the radiological control following the four cycles of double CHT and during CHT maintenance, there was a further reduction of the disease. This report aims to raise awareness among physicians about these serious side effects. A multidisciplinary approach led to clinical improvement and early intervention, optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Older patients with coronary artery disease (CAD) are particularly vulnerable to the efficacy and adverse drug reactions, and may therefore particularly benefit from personalized medication. Drug–gene interactions (DGIs) occur when an individual's genotype affects the pharmacokinetics and/or pharmacodynamics of a victim drug. Objectives: This study aimed to investigate the impact of cardiovascular-related DGIs on the clinical efficacy and safety outcomes in older patients with CAD. Methods: Hospitalized older patients (≥ 65 years old) with CAD were consecutively recruited from August 2018 to May 2022. Eligible patients were genotyped for the actionable pharmacogenetic variants of CYP2C9, CYP2C19, CYP2D6, CYP3A5, and SLCO1B1, which had clinical annotations or implementation guidelines for cardiovascular drugs. Allele frequencies and DGIs were determined in the cohort for the 5 actionable PGx genes and the prescribed cardiovascular drugs. All patients were followed up for at least 1 year. The influence of DGIs on the cardiovascular drug-related efficacy outcomes (all-cause mortality and/or major cardiovascular events, MACEs) and drug response phenotypes of "drug-stop" and "dose-decrease" were evaluated. Results: A total of 1,017 eligible older patients with CAD were included, among whom 63.2% were male, with an average age of 80.8 years old, and 87.6% were administrated with polypharmacy (≥ 5 medications). After genotyping, we found that 96.0% of the older patients with CAD patients had at least one allele of the 5 pharmacogenes associated with a therapeutic change, indicating a need for a therapeutic change in a mean of 1.32 drugs of the 19 cardiovascular-related drugs. We also identified that 79.5% of the patients had at least one DGI (range 0–6). The median follow-up interval was 39 months. Independent of age, negative association could be found between the number of DGIs and all-cause mortality (adjusted HR: 0.84, 95% CI: 0.73–0.96, P = 0.008), and MACEs (adjusted HR: 0.84, 95% CI: 0.72–0.98, P = 0.023), but positive association could be found between the number of DGIs and drug response phenotypes (adjusted OR: 1.24, 95% CI: 1.05–1.45, P = 0.011) in the elderly patients with CAD. Conclusions: The association between cardiovascular DGIs and the clinical outcomes emphasized the necessity for the integration of genetic and clinical data to enhance the optimization of cardiovascular polypharmacy in older patients with CAD. The causal relationship between DGIs and the clinical outcomes should be established in the large scale prospectively designed cohort study. [ABSTRACT FROM AUTHOR]