Search

Purpose: The recognition of adverse drug reactions (ADRs) is an important part of daily clinical work. However, medical education in this field is mostly drug-based and does not address adequately the complexity of this field regarding individual risk factors and polypharmacy. This study investigates the potential of the web-based serious game SeeMe (side-effect exposure—medical education) in pharmacological education of medical students to improve the recognition of relevant ADRs. Methods: One hundred fifty-seven medical students were recruited to evaluate the serious game SeeMe. SeeMe was developed to improve knowledge and recognition of ADRs in clinical practice. Players take on the role of a physician trying to understand fictional patients with ADRs. Before and after an 8-week playing period, an evaluation was carried out through a pre- and post-questionnaire and a pre- and post- knowledge test. Results: The students achieved significantly better results in the knowledge test, as almost twice as many exam-relevant questions were answered correctly (p < 0.001). The serious game had a positive effect on the students' perception of the importance of ADRs. Conclusion: This study demonstrates the potential of web- and case-based fictional serious games in medical education. The improved recognition of side effects represents a crucial step for education and training in clinical pharmacology. Future versions of the serious game may take this further and focus on training in the treatment of ADRs and their relevance in various healthcare professions. [ABSTRACT FROM AUTHOR]

Objective: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best‐evidenced substance used off‐label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP‐guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age‐ and disorder‐specific therapeutic reference range. Method: Sixty‐five adolescents with AN (aged 10–18) treated with OLZ (98% female; 97.5% AN‐restricting‐type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. Results: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. Conclusions: OLZ in the hands of specialists is a well‐tolerated and safe treatment adjunct for adolescents with AN. Highlights: Olanzapine in adolescents with anorexia nervosa is a safe and well‐tolerated adjunct to a multidisciplinary inpatient treatment approach using therapeutic drug monitoring.Correlations of dosage and serum levels are high.A preliminary disorder‐ and age‐specific reference range was successfully defined for the first time. [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]

ABSTRACT Biological agents are widely used across medicine, including for immune‐mediated skin conditions such as psoriasis and atopic dermatitis. When used to treat a relevant pathological process, they demonstrate impressive efficacy and credible safety, helping to achieve remission and improved function and quality of life. However, with their expanded use, awareness and understanding of adverse reactions to biologicals have also increased. Herein, we discuss the pathomechanism of adverse reactions to biological agents used to treat skin conditions and apply these to Pichler's classification system. This classification differentiates five distinct types, namely overstimulation (type α), hypersensitivity or immunogenicity (β), immunodeviation (γ), cross‐reactivity (δ) and nonimmunologic adverse reactions (ε). This classification covers most types of adverse reactions associated with use of biological agents and could be used to better understand the reaction pathogenesis and manage the clinical features of biological adverse effects. [ABSTRACT FROM AUTHOR]

Background/Objectives: Proton pump inhibitors (PPIs) are amongst the most commonly prescribed classes of medication. However, inappropriate PPI use can lead to several adverse drug reactions (ADRs). Limited data exist on factors contributing to the risk of ADRs associated with PPI prescribing patterns in the Eastern Region of Saudi Arabia. This retrospective, cross-sectional study aimed to assess the prevalence and the pattern of PPI use and to identify factors contributing to the risk of ADRs. Methods: Data were collected from electronic medical records of patients at Al-Qateef Central Hospital from January 2020 to December 2021. The inclusion criteria included patients aged ≥40 years attending an outpatient medical care clinic. PPI prescribing patterns were categorized based on their dosage intensity into low-dose, medium-dose (MD), and high-dose (HD) categories. Binary and multinominal logistic regression models were used to determine the relationship between PPI prescribing patterns and use, categorized by MD or HD, and patient characteristics, adjusted for significant covariates. Results are presented as adjusted odds ratio (OR) with corresponding 95% confidence intervals (95% CI). Results: The study included 41,084 patients. The prevalence of PPI prescribing was 31%. PPI users were more frequently found to be females than males (52% vs. 50%, p = 0.013); they were also likely to be prescribed more medications (7 vs. 6, p < 0.001), but less likely to have gastritis-related diseases (34% vs. 32%, p < 0.001) compared to non-users. PPI HD users were more likely male (56% vs. 43%, p < 0.001), older (53 vs. 52 years, p < 0.001), and prescribed more medications (11.8 vs. 2.8, p < 0.001) compared to MD users. PPI usage was associated with concurrent use of antiplatelet drugs (OR = 1.08, 95% CI 1.01–1.15). An increasing number of prescribed medications was associated with HD usage (OR = 1.13, 95% CI 1.12–1.14), but negatively associated with MD usage (OR = 0.7 95% CI 0.69–0.71). Female gender was negatively associated with HD usage (OR = 0.85, 95% CI 0.79–0.91). Conclusions: Our findings indicate that 31% of the included cohort were prescribed PPI. Inappropriate PPI prescribing related to the drug's omission is a concern as PPI non-users presented with valid indications such as gastritis. Male gender and increasing NPM were the common factors contributing to increased risk of PPI ADR. This study points to the importance of re-evaluating PPI use to ensure effective therapy with minimum risks of ADR. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study is to compare the adverse events (AEs) associated with pralsetinib and selpercatinib. Methods: To evaluate the imbalance of AEs linked to pralsetinib and selpercatinib in real-world data, the reporting odds ratio (ROR) was utilized to detect potential signals of AEs. Stratified analysis was conducted to examine the differences in AEs occurring among different genders and age groups taking pralsetinib and selpercatinib. Results: FAERS received 891 reports for pralsetinib and 569 reports for selpercatinib. Our analysis confirmed expected AEs like hypertension, fatigue, and elevated transaminase levels. Unexpected AEs such as rhabdomyolysis, myocardial injury and cognitive disorder were associated with pralsetinib, while selpercatinib was linked with pulmonary embolism, deep vein thrombosis, and pericardial effusion. The risk of AEs such as decreased platelet count, anemia, decreased white blood cell count, pneumonitis, asthenia, and edema caused by pralsetinib is significantly higher than that of selpercatinib. In contrast, the risk of AEs such as ascites, elevated alanine aminotransferase, and elevated aspartate aminotransferase caused by selpercatinib is significantly higher than that of pralsetinib. Women treated with pralsetinib experience higher rates of hypertension, pulmonary embolism, and blurred vision than men, who are more susceptible to rhabdomyolysis. Adults between 18 and 65 years are more likely to experience taste disorder, edema, and pulmonary embolism than individuals older than 65, who are particularly vulnerable to hypertension. For patients treated with selpercatinib, males demonstrate a significantly higher incidence of QT prolongation, urinary tract infection, and dysphagia. Individuals aged 18 to 65 are more likely to experience pyrexia and pleural effusion than those older than 65, who are more prone to hypersensitivity. Conclusion: In the clinical administration of pralsetinib and selpercatinib, it is crucial to monitor the effects of gender and age on AEs and to be vigilant for unlisted AEs. [ABSTRACT FROM AUTHOR]

Introduction: The discovery of serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9) has revolutionized pharmacological lipid-lowering treatments. The first PCSK9 antagonists (PCSK9-A), evolocumab and alirocumab, were approved in 2015. Targeting PCSK9 synthesis marked a major advancement in this field, leading to the development of inclisiran, a long-acting siRNA targeting PCSK9 mRNA. However, real-world safety data on this drug are still limited. Therefore, this study aims to provide a real-world safety evaluation of inclisiran, comparing its characteristics to those of PCSK9-As. Methods: A retrospective pharmacovigilance study was conducted using EudraVigilance (EV). Inclisiran-related individual case safety reports (I-ICSRs) from 01/01/2021 to 06/30/2023 were retrieved. ICSRs for evolocumab or alirocumab from 01/01/2015 to 06/30/2023 were collected as a reference group (RG). ADRs were classified using the MedDRA dictionary. Data were evaluated using descriptive and disproportionality analyses. Crude reporting odds ratio (ROR) with 95% confidence intervals (CI) were used as disproportionality measures. Results: Of the 15,236 ICSRs, 3.7% (n = 563) involved inclisiran, with the rest in the RG. Most I-ICSRs involved female patients (51.7%) aged 18 to 64 (52.8%). The most-reported ADRs for inclisiran were "general disorders and administration site conditions" (n = 347) and "investigations" (n = 277). Significant disproportionality was found in I-ICSRs compared to the RG for "Myalgia" (ROR: 2.43; 95% CI: 1.94–3.04), "Low-density lipoprotein increased" (ROR: 11.95; 95% CI: 9.10–15.52), and "Drug ineffective" (ROR: 6.37; 95% CI: 4.64–8.74). Conclusions: The inclisiran safety profile aligns with the existing literature and pre-commercial data. However, further studies are needed to fully understand the observed differences with PCSK9-As. [ABSTRACT FROM AUTHOR]

Ageing is associated with an increased risk of adverse drug reactions. This calls for great care and diligent follow up when prescribing medication to older patients. Yet, this is seldom the case and the proportion of older people taking five or more medications has quadrupled from 12% to 49% in the last 20 years. Certain medications are riskier than others. Those with anticholinergic effects are of particular concern. Adverse effects of anticholinergics include dry mouth, nausea, dizziness, fatigue, vomiting, constipation, abdominal pain, urinary retention, blurred vision, tachycardia and neurologic impairment, such as confusion and agitation. Anticholinergic medication can cause daytime drowsiness and cognitive decline, while increasing the risk of fall and can lead to increased mortality. Although anticholinergic medication should be avoided in older people whenever possible, their use has almost doubled in the last 20 years, and those who are most vulnerable to its adverse effects had the greatest increase in use. This article examines why older people are at increased risk of adverse drug reactions and how medication review can enable older persons to take medications regularly, improve quality of life and minimise medication waste. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading cause of death globally, making the use of oral anticoagulants for prevention increasingly important. Historically, warfarin has played a significant role in this context. In recent years, introduction of new oral anticoagulants, such as rivaroxaban, apixaban, dabigatran, and edoxaban, has been seen. This study evaluates the risk associated with the use of oral anticoagulants by analyzing spontaneous adverse drug reactions reported to the Portuguese Pharmacovigilance System from 2012 to 2021. The study includes 951 adverse drug reactions reports, with the majority (n = 770; 80.97%) classified as serious. Of the 770 serious adverse drug reactions reports, the most commonly reported seriousness criterion was "Clinically Important" (n = 350; 45.45%). In terms of demographics, there was a higher reporting rate among the elderly population, with a greater prevalence of females. The System Organ Class group with the highest number of adverse drug reactions was "Gastrointestinal disorders," with the most commonly reported Preferred Term being "Gastrointestinal hemorrhage," and dabigatran was the most frequently reported drug. In summary, oral anticoagulants have adverse drug reactions that require continuous monitoring. Accurate identification and monitorization of adverse drug reactions is an important starting point to improve drug safety in population. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs. Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs. Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged. Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Hospitalizations for adverse drug reactions (ADR‐HA) have increased over the last decade, but the impact of ADR‐HA has rarely been evaluated. The aim of this study was to estimate the economic burden of ADR‐HA in France.A partial economic evaluation from the viewpoint of French public health insurance was performed, based on a previous pharmacovigilance study (IATROSTAT) performed in 2018 in public hospital medical units. The cost included direct medical costs, collected retrospectively, from the French hospital discharge database. The economic burden was estimated by calculating the total cost per ADR‐HA patient (cost of hospital stays, additional daily cost of specific stays, such as in a resuscitation, intensive care or continuous surveillance unit, drug products and medical devices in addition to Healthcare Resource Group‐based tariffs, and specific outpatient consultations and other clinical and technical medical procedures, over 3 months as from the first day of ADR‐HA). The robustness of the results was assessed using a one‐way deterministic sensitivity analysis of cost factors applying tariffs from 2023 instead of 2018.According to the 2018 tariffs (vs. 2023), the mean total cost per patient with ADR‐HA was estimated at €5208 ± €3719 (vs. €5974 ± €4232) ranging from €514 to €23 355 (vs. €618 to €27 380). The total cost for 196 patients with ADR‐HA admitted to a sample of French public hospitals was estimated at €1 020 549 (vs. €1 170 960). It could be estimated at €1.3 billion at the national level.In addition to the increase in the number of expensive drugs, the ageing population and polypharmacy, the economic impact of serious ADR‐HA weighs heavily on healthcare spending. [ABSTRACT FROM AUTHOR]

Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016–2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019–2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4–8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3–63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: Immune Thrombocytopenia Purpura (ITP) is a hematological disorder, where its primary cause is unknown. This can be triggered through any secondary underlying diseases or other environmental agents such as drugs, vaccination, natural viral infections etc. After the introduction of COVID-19 vaccines, a 4-fold increase in ITP cases was observed globally. Many of the COVID-19 vaccines such as m-RNA and viral-vector vaccines already demonstrated a cause-effect relationship between the event of ITP and immunization. Case presentation: A 54 year old diabetic patient presented to the hospital with complaints of gum bleeding and fatigue. He was diagnosed with severe ITP following COVID-19 vaccination with a platelet count of 5000 cumm. Initially his condition was considered as idiopathic and the COVID-19 vaccine exposure (13 days prior to the clinical presentation) was not suspected. Later the immunization timeline and onset of the reaction was traced by his hematologist. The patient underwent multiple platelet transfusions and was given corticosteroid therapy. The patient was followed for a period of 1 year and throughout the follow-up period the patient had fluctuating platelets count, especially after tapering steroids. Conclusion: ITP in this case is found to have a consistent causal association to COVID-19 vaccination as per the World Health Organization Causality assessment algorithm and is categorized under vaccine product related reactions. One year follow-up conducted showed that the thrombocytopenia following COVID-19 vaccine may be prolonged. [ABSTRACT FROM AUTHOR]

Ferric carboxymaltose (FCM) allows for rapid and total correction of iron deficiency with a lower risk of hypersensitivity reactions compared to other IV iron preparations. However, FCM is associated with potentially serious adverse events, including hypophosphatemia, following the infusion. The mechanism behind FCM-induced hypophosphatemia is not well understood, but pre-existing risk factors can increase the likelihood of severe and persistent hypophosphatemia. We report a clinical case of a male patient who developed severe hypophosphatemia (1.0 mg/dL) after administration of FCM for the treatment of post-cardiotomy normocytic anemia. He required hospital admission and 16 weeks of phosphorous supplementation. [ABSTRACT FROM AUTHOR]

Aim: Evaluating the impact of vitamin K prophylaxis on cefoperazone-sulbactam-induced coagulopathy in critically ill patients. Methods: We conducted a randomized controlled trial on critically ill adult patients treated with cefoperazone-sulbactam. Patients received systemic cefoperazone-sulbactam antibiotics of 1.5 to 2 g every 12 hours. Patients were randomized into 2 groups: the intervention group (Gp-I), who received a 10 mg intravenous dose of vitamin K every week until cefoperazone-sulbactam therapy ended, and the control group (Gp-C), who received only cefoperazone-sulbactam. Results: Our main finding was the significantly higher survival probability from coagulopathy in Gp-I than in Gp-C using the Kaplan-Myers curve (χ2 = 25.5, P <.001). The adjusted hazard ratios for coagulopathy obtained from the Cox regression analysis revealed that the intervention was significantly associated with a 99% reduction in the hazard of coagulopathy relative to Gp-C (HR = 0.01, P =.001). The Kaplan-Myers curve indicated a significantly higher survival probability from bleeding in Gp-I than in Gp-C (χ2 = 9, degree of freedom = 1, P =.005). Conclusion: In critically ill patients, intravenous prophylactic doses of vitamin K of 10 mg per week prevent cefoperazone-sulbactam-induced coagulopathy. Therefore, we recommend adding vitamin K supplementation to ICU protocols in Egypt for cefoperazone-sulbactam safety. [ABSTRACT FROM AUTHOR]

Purpose: Adverse Drug Reactions (ADR) classification is useful in modern medical diagnostics and related applications. ADR is an example of how medical information is frequently accessible on social media platforms for healthcare, where people can share their experiences with treatments on desktop computers and mobile devices. Many researchers are interested in gathering valuable medical data from social media for the ADR system training and classification process. Materials and Methods: This research explores the effects of three aspects on recognizing ADR mentions in social media for the medical field and proposes a deep neural network of Long Short-Term Memory (LSTM) neural networks to do so. The comments are collected from various social media platforms to implement the ADR system with proper training and testing processes. The texts from the dataset are initially preprocessed by using a data filtering and clustering process to remove the input data's redundant information to increase the training process's quality. Characteristic features, such as semantic features and text statistics, are extracted from the input text using the American Standard Code for Information Interchange (ASCII) array. Further, the features are converted and fed to LSTM networks for training and validation. Results and Conclusion: This work is evaluated using two datasets, CODEC, and ADR Corpus datasets are used to evaluate the performance of the proposed ADR technique via multiple angles. Via extensive experiments, this work achieved 99.79 accuracy, 98.37 sensitivity, 97.63 specificity, 99.72 precision, 98.39 recall, 97.62 F1-score for the CODEC dataset, 98.16 for accuracy, 99.19 for sensitivity, 98.49 for specificity, 99.49 for precision, 96.72 for recall, and 93.16 for F1-score for ADR corpus, respectively. [ABSTRACT FROM AUTHOR]

Background: Intranasal corticosteroids (INCS) are used for several conditions, including allergic rhinitis and sinusitis. Consequently, their safety profile needs continuous monitoring. This study aimed to analyse the adverse drug reactions (ADRs) of the INCS with market authorisation in Europe. Methods: A retrospective analysis of the ADR data from EudraVigilance in the period between the 1 January 2011 and 12 June 2023 was performed, with 2641 reports selected for analysis. ADRs were categorised by seriousness and evolution, with a focus on the most prevalent ADRs and their alignment with the Summary of Product Characteristics (SmPC). Results: The 18–64 age group, particularly females, was most affected. Mometasone was the most reported INCS, with predominantly non-serious ADRs, evolving towards resolution, which often were not listed in the SmPC. From the reported ADRs that were not described in the SmPC of the INCS studied, "Anosmia" and "Ageusia" were highlighted. Regarding the ADRs described in the SmPC, the most frequently reported were "Epistaxis" and "Headache". The ADRs belonging to the Designated Medical Event list were also analysed, with "Angioedema" as the most reported ADR, which was mainly associated with budesonide. Conclusions: These findings underscore the importance of continuous INCS monitoring to mitigate ADRs and safeguard public health. Further research is warranted to explore potential novel signs for safety arising from previously unreported ADRs. [ABSTRACT FROM AUTHOR]

Objectives: Adverse drug reactions (ADRs) are a major drug safety concern and a frequent topic of enquiries to hospital drug information services. Our goal was to analyse these enquiries regarding background, complexity, nature of ADR, and involved drug classes to improve in-hospital drug safety. Methods: Retrospectively, ADR enquiries to a German university hospital pharmacy drug information 2018–2022 were analysed regarding enquirer (profession, medical specialty) and enquiry details (drugs, suspected ADR/enquiry prior to drug initiation, ADR system organ class, probable cause identified, and enquiry complexity). Key findings: Of 543 enquiries, 516 (95%) were asked by physicians, 493 (91%) patient-specific, 390 (71%) on suspected ADRs, and 153 (28%) prior to drug initiation. Enquiries originated frequently from internal medicine (74/13.6%), paediatrics (71/13.1%), neurology (70/12.9%), and haemato-oncology (62/11.4%). Most frequent ADRs were haematologic (94/17%) and hepatic (72/13%). The median number of drugs per enquiry was three (range 0–37), 209 (38%) enquiries referred to one specific drug, 165 (30%) concerned ≥11 drugs. A probable cause for suspected ADRs was identified in 75 (36%) enquiries concerning one drug and 155 (94%) with ≥11 drugs. Most frequent drugs were antineoplastic (54/25.8%), nervous-system-drugs (42/20.1%), and anti-infective (40/19.1%). Most enquiries (342/63%) were complex (multiple/specialist resources). Conclusions: Enquiries were usually asked by physicians referring to suspected ADRs in specific clinical situations. A probable cause was identified in many cases pointing to a direct positive impact on patient care. Enquiries prior to drug initiation should be encouraged to increase drug safety. Information on main ADR effects and drug classes helps with targeted counselling. [ABSTRACT FROM AUTHOR]

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak, which causes COVID-19, had a devastating impact on both people's lives and the global economy. During the course of the pandemic, the lack of specific drugs or treatments tailored for COVID-19 led to extensive repurposing of existing drugs in the pursuit of effective treatments. Some drug molecules demonstrated efficacy, while others proved ineffective. In this context, the approach of drug repurposing emerged as a novel strategy for combating COVID-19. Repurposed drugs and biologics have shown effectiveness, leading to improved clinical outcomes among patients with COVID-19. Similarly, It is equally important to assess the risk–benefit ratio associated with drugs and biologics adapted for COVID-19 treatment. Herein, we primarily focus on evaluating adverse drug events linked to repurposed COVID-19 medications, repurposed biologics, and COVID-specific drug molecules. [ABSTRACT FROM AUTHOR]

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. Data sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. Study selection and data extraction: Relevant English-language clinical trials were evaluated. Data synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. Relevance to patient care and clinical practice in comparison with existing drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Immune checkpoint inhibitors, such as nivolumab, combined with small molecule antiangiogenic receptor tyrosine kinase inhibitors (TKIs), present a promising strategy for future immunotherapy. However, combination therapy can lead to specific adverse drug reactions (ADRs) in various clinical settings. Current research on the ADRs associated with combination therapy is limited. Our study aims to assess the safety of combination therapy.We extracted ADR reports on combination therapy from the Food and Drug Administration (FDA) Adverse Event Reporting System database, covering the period from the first quarter of 2012 to the third quarter of 2023, and conducted a large‐scale retrospective study. We evaluated ADR risk signals using the reporting odds ratio (ROR) and calculated the Ro/e ratio to compare the differences in the risk of fatal ADRs among various tumour types.We comprehensively reported the occurrence of ADRs in pan‐cancer patients undergoing combination therapy. The combination therapy significantly increased the risk of sensitive skin (ROR: 231.43, 95% CI: 55.01–973.72, P < .05), metastatic renal cell carcinoma (ROR: 220.71, 95% CI: 28.99–1695.41, P < .05) and renal cell carcinoma (ROR: 188.22, 95% CI: 44.24–800.85, P < .05). We also compared the differences in ADRs resulting from different small molecule drug combinations, as well as the differences in ADRs among patients with different types of tumours under combination therapy. Furthermore, we analysed the characteristics of patients prone to experiencing fatal ADRs.These results can help enhance understanding of the ADRs commonly associated with combination therapy and assist oncologists in formulating screening protocols. [ABSTRACT FROM AUTHOR]

Background Objective Method Results Limitations Conclusion Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by targeting immune checkpoints such as PD‐1, PDL‐1, and CTLA‐4, but concerns about severe immune‐related adverse events persist. The scarcity of literature on dermatologic implications, especially severe reactions such as Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), highlights the urgent need for investigation.Our systematic review aims to address the gap in relevant literature by extensively examining the epidemiologic risk factors and management of SJS/TEN‐like illnesses in ICI‐treated patients to provide insights for risk assessment and clinical care.We identified 158 case reports that detailed the incidence of SJS/TEN in patients being treated with ICIs, examining demographic patterns, type of malignancy, clinical characteristics, and treatments linked to onset. We assessed mortality rates, risk elements, and the effectiveness of interventions to help guide clinical care.Analysis of 158 case reports revealed that SJS/TEN in ICI users is typically seen on average at the age of 63 and is more common in males. PD1 inhibitors such as nivolumab and pembrolizumab are often associated with various mucocutaneous patterns and significant risks with ICI use, especially TEN, which is linked to high morbidity and mortality rates.Our study notes limitations due to the inclusion of case reports or case series, such as potential publication and reporting biases, leading to skewed findings. Additionally, because of the heterogeneous reporting standards, the retrospective nature limits phenotypic precision, control for confounding variables, and data completeness.Our study provides valuable insights into the epidemiology, clinical features, management strategies, and outcomes of ICI‐induced SJS/TEN, underscoring the importance of vigilant monitoring and personalized risk assessment in oncology practice. Continued research efforts are essential to optimize patient outcomes and enhance the safety profile of ICIs in cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: We report a case of a patient experiencing paroxysmal supraventricular tachycardia after infusing doxophylline. Methods: Clinical evaluations and the electrocardiogram were performed by specialists. Findings: Our patient felt palpitations and chest distress after intravenous Doxophylline. The electrocardiogram showed paroxysmal supraventricular tachycardia. There was no evidence to prove that there was any problem with his heart, liver, and kidney. According to the Naranjo Adverse Drug Reaction probability scale, paroxysmal supraventricular tachycardia has a probable relationship with Doxophylline. Implications: The paroxysmal supraventricular tachycardia is a rare but reasonable adverse reaction of Doxophylline, which should be paid more attention. [ABSTRACT FROM AUTHOR]

Acute generalized exanthematous pustulosis, an infrequent adverse drug reaction, mainly results from drugs. Clinically, acute generalized exanthematous pustulosis manifests as a high fever, with skin lesions of small monomorphic subcorneal sterile pustules on an erythematous that presents at 1-4 days after medication exposure. The incidence of acute generalized exanthematous pustulosis varies from 3/1, 000, 000 to 5/1, 000, 000, while the mortality rate is typically around 5%. We present a case of a 69-year-old female who developed a diffuse, erythematous, pustular rash over the entire body and exhibited a fever of 38.3°C after 4 days of icotinib therapy. Considering her medication history and the appearance of the lesions, she was diagnosed with acute generalized exanthematous pustulosis and received appropriate treatment. We also conducted a literature review through PubMed to compare similarities and differences between our case and those reported in the literature. [ABSTRACT FROM AUTHOR]

Prior research has indicated that bisphosphonates (BPs) can improve periodontal disease because of their anti-osteoporosis properties. In vitro studies have shown that BPs induce cytotoxicity, inhibit wound healing, and thus affect periodontal disease. Denosumab and BPs have alternative indications. BP and denosumab are not known to correlate with gingival disorders. We assessed such a relationship by applying Bayesian and nonproportional analyses to data in the US FDA Adverse Event Reporting System (FAERS) database. The study analyzed BPs and denosumab-reported incidents with preferred terms found in the narrow Standardized MedDRA Queries for gingival disorders. A total of 5863 reported cases of gingival disorders were associated with five BPs (alendronate, pamidronate, ibandronate, risedronate, and zoledronate) and denosumab. More than 15% of patients with gingival disorders related to BPs and denosumab other than denosumab were hospitalized over short- or long-term periods. Our findings indicated BPs and denosumab had significant reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) with respect to gingival disorders. Pamidronate had the highest association (ROR = 64.58, PRR = 57.99, IC = 5.71), while the weakest association was found with denosumab (ROR = 3.61, PRR = 3.60, IC = 1.77). Significant associations were found between the six drugs and gingival pain, gingival recession, gingivitis, periodontal disease, and periodontitis. In conclusion, our comprehensive overview of the correlations, clinical characteristics, and prognoses of BPs and denosumab-related gingival disorders suggests that these issues deserve continued surveillance and appropriate management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into clinical efficacy and safety of different doses of tacrolimus eye drops in the treatment of patients with keratoconjunctivitis. METHODS: A randomized, open cohort study was adopted. Totally 89 patients with keratoconjunctivitis admitted into Hubei Third People’s Hospital Affiliated to Jianghan University from Mar. 2021 to Mar. 2023 were extracted to be divided into low-dose group (n = 44) and conventional dose group (n =45) by random number table method. Tacrolimus eye drops were used once a day in the low-dose group and twice a day in the conventional dose group. All patients were treated continuously for 6 months. The scores of ocular symptoms and signs were compared between two groups before treatment, after treatment of 1 month, 3 months and 6 months. The inflammation levels [C-reactive protein (CRP), interleukin (IL)-2, IL-6], best corrected vision and intraocular pressure (IOP) were compared between two groups before treatment and after treatment of 6 months. The clinical efficacy and adverse events were compared between two groups. RESULTS: After treatment of 1 month and 3 months, the scores of ocular symptoms and signs in the conventional dose group were significantly lower than those in the low-dose group, with statistically significant differences (P <0. 05). After treatment of 6 months, there was no statistically significant difference between two groups in the scores of ocular symptoms and signs (P >0. 05). After treatment of 6 months, there was no statistically significant difference in serum CRP, IL-2, IL-6, IOP and best corrected vision between two groups (P>0. 05). The total effective rate of conventional dose group and low-dose group was respectively 91. 11% (41/45) and 88. 64% (39/44), with no statistically significant difference (P>0. 05). The incidence of adverse events in the low-dose group was 4. 55% ( 2/44), lower than 11. 11% ( 5/45) in the conventional dose group, the difference was not statistically significant (P>0. 05). CONCLUSIONS: The effects of low-dose tacrolimus in improving the clinical symptoms and signs of keratoconjunctivitis in the short term is less than that of conventional dose regimen, yet the long-term clinical efficacy is not affected, and the incidence of adverse events is lower when using low-dose tacrolimus, which has certain clinical application prospects. [ABSTRACT FROM AUTHOR]

• CF treatment is complex requiring an average of 10 daily medications, increasing the risk for drug therapy problems (DTP). • 75 % of PwCF demonstrated actionable PGx interventions, enabling 4.2 potential treatment modifications per 10 PwCF. • CYP2D6 and CYP2C19 polymorphisms majorly contribute to DTPs in PwCF, guiding pharmacotherapy. • Pharmacogenetic (PGx) panel testing shows promise in reducing DTPs, thereby personalizing medication care plans and improving treatment outcomes in people with cystic fibrosis (PwCF). With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug therapy problems (DTPs), and interference with treatment goals. Given that some of these DTPs can be prevented with preemptive pharmacogenetic testing, the overall goal of this study was to test the clinical utility of a multi-gene pharmacogenetics (PGx) panel in potentially reducing DTPs in PwCF. A population based retrospective study of patients with CF was conducted at the University of Utah Health Care System. The patients were genotyped for CYP450 enzymes using a pharmacogenomic assay, and their drug utilization information was obtained retrospectively. This pharmacogenomic information was combined with clinical guidelines to predict the number of actionable PGx interventions in this patient cohort. A total of 52 patients were included in this study. In the patient sample, a minimum of one order of actionable PGx medication was observed in 75 % of the cases. Results revealed that 4.2 treatment modifications per 10 patients can be enabled with the help of a PGx intervention in this patient population. Additionally, our findings suggest that polymorphisms in CYP2D6 and CYP2C19 are most likely to be the primary contributors to DTP's within PwCF. This study provides evidence that the PGx panel has the potential to help alleviate the clinical burden of DTPs in PwCF and can assist in informing pharmacotherapy recommendations. Future research should validate these findings and evaluate which subgroups of PwCF would most benefit from pharmacogenetic testing. [ABSTRACT FROM AUTHOR]

Aims: This systematic review aimed to investigate the occurrence of moderate and severe adverse drug reactions (ADRs) to antimicrobials among hospitalized children. Methods: The PubMed/Medline, Cochrane Library, Embase, Web of Science, Scopus, Lilacs and CINAHL databases were searched in April 2023 to systematically review the published data describing the characteristics of moderate and severe ADRs to antimicrobials among hospitalized children. The search was carried out without date restrictions, up to the search date (April, 2023). Results: At the end of the selection process, 30 articles met the inclusion criteria. Cutaneous reactions were the primary serious clinical manifestations in most articles (19/30), followed by erythema multiforme (71 cases), Stevens–Johnson syndrome (72 cases), and toxic epidermal necrolysis (22 cases). The main antimicrobials involved in moderate and severe ADRs were penicillins, cephalosporins and sulfonamides. Regarding the primary outcomes, 30% (9/30) of the articles reported deaths, and 46.7% (14/30) of studies reported increased lengths of hospital stay, need for intensive care, and transfer to another hospital. Regarding the main interventions, 10% (3/30) of the articles mentioned greater monitoring, suspension, medication substitution or prescription of specific medications for the symptomatology. Conclusions: The findings of this review could be used to identify areas for improvement and help health professionals and policymakers develop strategies. In addition, we emphasize the importance of knowing about ADRs so that there is adequate management to avoid undesirable consequences. [ABSTRACT FROM AUTHOR]

Posterior reversible encephalopathy syndrome (PRES) is an acute neurological condition associated with different etiologies, including antibiotic therapy. To date, most data regarding antibiotic-related PRES are limited to case reports and small case series. Here, we report a novel case description and provide a systematic review of the clinico-radiological characteristics and prognosis of available cases of PRES associated with antibiotic therapy. We performed a systematic literature search in PubMed and Scopus from inception to 10 January 2024, following PRISMA guidelines and a predefined protocol. The database search yielded 12 subjects (including our case). We described the case of a 55-year-old female patient with PRES occurring one day after administration of metronidazole and showing elevated serum neurofilament light chain protein levels and favorable outcome. In our systematic review, antibiotic-associated PRES was more frequent in female patients (83.3%). Metronidazole and fluoroquinolones were the most reported antibiotics (33.3% each). Clinical and radiological features were comparable to those of PRES due to other causes. Regarding the prognosis, about one third of the cases were admitted to the intensive care unit, but almost all subjects (90.0%) had a complete or almost complete clinical and radiological recovery after prompt cessation of the causative drug. Antibiotic-associated PRES appears to share most of the characteristics of classic PRES. Given the overall good prognosis of the disease, it is important to promptly diagnose antibiotic-associated PRES and discontinue the causative drug. [ABSTRACT FROM AUTHOR]

The present landscape of adverse drug reactions (ADRs) cases paints a somber picture, with statistics indicating that a substantial proportion of hospital admissions result from patients experiencing drug side effects. The existing solutions for preventing and monitoring ADRs, however, seem to operate in isolation. Addressing these gaps calls for the creation of a fully integrated platform for preventing and monitoring ADRs. Central to the success of such a platform is understanding user needs. This research focused on identifying functional needs for physicians and patients, along with non-functional requirements from hospital information system providers. This study employs a user-centered design methodology structured around a series of key steps that collectively guide the process of user needs and requirement identification and analysis. For an overarching view of the functional requirements, questionnaires were utilized to engage both physicians and patients. For gathering non-functional requirements interviews were conducted with Hospital Information System Providers. 37 physicians and 40 patients participated in the survey. Physicians favored Drug Information Checker, Drug-to-Drug Interaction Checker, Patient ADR Report history-based drug checker, and other general features. Patients prioritized ADR Reporting, Medication Reminders, and mobile platform accessibility. Additionally, two hospital system experts highlighted non-functional prerequisites, including interoperability, security, usability, availability, and performance. This study focus encompassed three pivotal actors: physicians, patients, and hospital information system providers. Physicians and patients lent insights into functional requirements that mirror their clinical and personal journeys, respectively. Meanwhile, the contributions of hospital information system providers illuminated the non-functional aspects imperative for a seamlessly integrated platform. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the incidence of and potential risk factors for adverse drug reactions (ADRs) after non-ionic iodinated contrast media (NICM) administration for CT exams in out-patient settings in China. Materials and methods: A total of 473,482 out-patients who underwent intravenous NICM between January 1st, 2017, and Dec 31st, 2021, were retrospectively enrolled from three institutions. The occurrence of ADRs and clinical information were recorded. Chi-square test, Poisson regression, and logistic regression analyses were used to evaluate potential ADR risk factors and correlation with demographics, season, and NICM type. Results: Among the 473,482 patients (mean age 55.22 ± 14.85; 253,499 male) who received intravenous NICM, the overall ADR incidence was 0.110% (522 of 473,482), with 0.099% acute-related drug reactions (469 of 473,482) and 0.0004% serious ADRs (two of 473,482). Iopromide was associated with a higher risk of acute ADRs. Late ADRs were more frequently observed with iodixanol 320. Multi-level logistic regression of patients with acute ADRs and a control group (matched 1:1 for age, gender, NICM, prescriber department, and institution) showed that summer (adjusted OR = 1.579; p = 0.035) and autumn (adjusted OR = 1.925; p < 0.001) were risk factors of acute ADRs. However, underlying disease and scanned body area were not related to a higher ADR incidence. Conclusion: The use of NICM for out-patients is in general safe with a low ADR incidence. The type of contrast medium (iopromide) and the seasons (summer and autumn) were associated with a higher risk of acute ADRs. Late ADRs were more often observed with iodixanol. Clinical relevance statement: In comparison to in-patients, out-patients may be exposed to higher risk due to a lack of extensive risk screening, less nursing care, and higher throughput pressure. Safety data about NICM from a large population may complement guidelines and avoid ambiguity. Key Points: • The incidence and risk factors for adverse events after using non-ionic iodinated contrast media are complex in out-patients. • Non-ionic iodinated contrast media are safe for out-patients and the overall incidence of adverse drug reactions was 0.110%. • There is a higher risk of acute adverse drug reactions in summer and autumn. [ABSTRACT FROM AUTHOR]

Background: Patients with dementia are prescribed low-dose atypical antipsychotics (AAPs) to treat psycho-behavioral symptoms. Although AAPs are known to cause diabetes mellitus–related adverse events (DMAEs), information regarding AAPs-induced DMAEs experienced by patients with dementia is lacking. Objective: To use the Japan Adverse Drug Event Report (JADER) database to assess the onset tendencies and patterns of DMAEs attributable to AAPs prescribed to patients with dementia. Methods: We performed an analysis using dementia cases from the JADER database that were registered from April 2004 to December 2022. Data in the JADER database are completely anonymized; thus, we did not require institutional review board approval for using the JADER database in our study. The reporting odds ratio and proportional reporting ratio (PRR) were used to assess the onset tendencies of DMAEs with AAPs. In addition, Weibull shape parameters were used to assess the patterns of DMAEs that occur with the use of AAPs. Results: We identified AAPs associated with DMAEs. In particular, low doses of quetiapine showed the potential to induce DMAEs. An analysis of the onset of DMAEs showed the early failure patterns for AAPs (median onset = 38 days). Conclusion and Relevance: The AAPs may cause DMAEs in patients with dementia. Low doses of quetiapine may induce DMAEs. Health care workers should focus on the development of DMAEs during the early administration period of AAPs. These results may assist with the safe management of patients with dementia who use AAPs. [ABSTRACT FROM AUTHOR]

Background/Aim: Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. Materials and Methods: To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. Results: We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). Conclusion: Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations. [ABSTRACT FROM AUTHOR]

Hind Alshehri,1 Adnan Alharbi,1 Noof Alqethami,2 Mohammed Alnuhait,1 Abdullah Alshammari,1 Abdulmalik S Alotaibi1 1Pharmaceutical Practices Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 2Clinical Pharmacy Department, Taif Health Cluster, King Faisal Medical Complex, Taif, Saudi ArabiaCorrespondence: Abdulmalik S Alotaibi, Email assalotaibi@uqu.edu.saBackground: Pharmacovigilance (PV) is an essential part of the healthcare system’s framework. In Saudi Arabia, pharmacovigilance is still a relatively new concept though it is well established in many countries.Study Aim: In this study, we aim to evaluate knowledge, attitude, and practice regarding pharmacovigilance and barriers to reporting adverse drug reactions (ADRs) among the general public in Saudi Arabia.Methods: This is a cross-sectional study that used a self-administered online questionnaire to assess knowledge, attitude, and practice of PV and ADRs. The study included only the adult population in Saudi Arabia. A scoring system was generated with a scale from 0 to 100, where 80% was set as a cut-off point, as any higher score resembled adequate knowledge, a positive attitude, and good practice. We used the Statistical Package for Social Sciences (SPSS) version 26 for performing the statistical analysis, where para-normal tests were used to associate scores with the socio-demographic characteristics of participants.Results: The study collected 1098 complete responses. The mean age (±SD) of participants was 37.9± 11.2 years. Females comprised 68.9% of the participants. The average knowledge score among participants was 37.8± 18.5, where only 4.3% of respondents had adequate knowledge. The average attitude score was 90.1± 19.2, where 83.4% had a positive attitude. The average practice score was 70.4± 18, and 34.5% of participants had good practice.Conclusion: The study found that the majority of participants had inadequate knowledge, a positive attitude, and poor practice. Individuals holding a master’s degree or higher and those working in the healthcare sector had the highest knowledge scores, whereas the group aged 31 to 50 years old, participants from the Al Jawf region, participants who are married with children, holders of a master’s degree or higher, and healthcare workers had the best attitude scores. Higher practice scores were seen among married individuals with children and those who work in the healthcare sector.Keywords: pharmacovigilance, adverse drug reactions, knowledge, attitude, practice, Saudi Arabia

Abstract This retrospective cross-sectional study aims to evaluate the safety, tolerability, and adherence of patients prescribed Nirmatrelvir-ritonavir (Paxlovid) in outpatient settings, focusing on its use in managing category 2 COVID-19 patients across three primary healthcare clinics in Selangor, Malaysia. Data were collected from the Paxlovid pharmacy registry and medical records at Klinik Kesihatan Seksyen 7, Klinik Kesihatan Seksyen 19, and Klinik Kesihatan Kelana Jaya between April 1, 2022, and November 30, 2022. This study analysed data from 415 category 2 COVID-19 patients aged ≥ 18 years. The primary and secondary outcomes included the assessment of patient demographics, Paxlovid dosing, current medication, changes in drug regimen, adherence, and adverse drug reactions (ADR). Pharmacists follow-ups were conducted on days 3 and 5 post-medication initiation. The majority (79.5%) of the cohort experienced ADR, predominantly dysgeusia, diarrhoea, body ache, vomiting, and nausea. Despite this, the ADRs were generally well-tolerated, with no severe impacts reported. High adherence was observed, with 96.9% of patients completing the 5-day regimen. The primary reasons for non-adherence included adverse effect intolerability, dosing ambiguity, forgetfulness, concerns about ADR, and perceived health improvement. Notable medications interacting with Paxlovid were simvastatin, amlodipine, and atorvastatin, and 21.7% of 23 concurrent medications were found not to comply with the recommended interventions by the University of Liverpool COVID-19 Drug Interaction database. Paxlovid demonstrates a high level of safety and tolerability in outpatient COVID-19 patients, with optimal adherence observed. This study underscores the vital role of healthcare professionals in managing Paxlovid within primary healthcare and highlights the need for broader research and direct patient involvement to enhance treatment strategies against COVID-19.

Abstract The presence of adverse drug reactions (ADRs) is an ongoing public health concern. While traditional methods to discover ADRs are very costly and limited, it is prudent to predict ADRs through non-invasive methods such as machine learning based on existing data. Although various studies exist regarding ADR prediction using non-clinical data, a process that leverages both demographic and non-clinical data for ADR prediction is missing. In addition, the importance of individual features in ADR prediction has yet to be fully explored. This study aims to develop an ADR prediction model based on demographic and non-clinical data, where we identify the highest contributing factors. We focus our efforts on 30 common and severe ADRs reported to the Food and Drug Administration (FDA) between 2012 and 2023. We have developed a random forest (RF) and deep learning (DL) machine learning model that ingests demographic data (e.g., Age and Gender of patients) and non-clinical data, which includes chemical, molecular, and biological drug characteristics. We successfully unified both demographic and non-clinical data sources within a complete dataset regarding ADR prediction. Model performances were assessed via the area under the receiver operating characteristic curve (AUC) and the mean average precision (MAP). We demonstrated that our parsimonious models, which include only the top 20 most important features comprising 5 demographic features and 15 non-clinical features (13 molecular and 2 biological), achieve ADR prediction performance comparable to a less practical, feature-rich model consisting of all 2,315 features. Specifically, our models achieved an AUC of 0.611 and 0.674 for RF and DL algorithms, respectively. We hope our research provides researchers and clinicians with valuable insights and facilitates future research designs by identifying top ADR predictors (including demographic information) and practical parsimonious models.

Background: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. Methods: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016–2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019–2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. Results: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4–8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3–63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P

INTRODUCTION. Pharmacotherapy in elderly and senile patients is associated with multimorbidity and polypharmacy and can lead to adverse drug reactions (ADRs). The growth of the world’s population over 60 makes the practical application of the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, the key recommendations to optimise prescribing in the geriatric population, increasingly important.AIM. This study aimed to review the history of the Beers criteria, the main changes in the updated 2023 version, and national and international publications on the practical experience of using the criteria in healthcare settings.DISCUSSION. The criteria for assessing the rationality of pharmacotherapy in older patients were developed by Mark Beers in 1991. His recommendations have been regularly reviewed and updated by a panel of experts from the American Geriatrics Society (AGS); version 7 has been in effect since 2023. The criteria are designed to support pharmacotherapy decision making for adults 65 years old and older in all ambulatory, acute, and institutionalised settings of care, except hospice and end-of-life care settings. The criteria are organised into 5 categories: 1) medications that should be avoided in all older adults; 2) medications considered potentially inappropriate in patients with certain diseases or syndromes; 3) medications that should be used with caution; 4) medications that are potentially inappropriate due to the risk of clinically significant drug–drug interactions; 5) medications that should be avoided or require dosage reduction in patients with impaired renal function. Medicines with pronounced anticholinergic effects are categorised as a separate class. The criteria are based on expert grading of the quality of evidence and strength of recommendations. Compared with the previous version (2019), the updated AGS Beers Criteria® (2023) changed the most in terms of recommendations for anticoagulants and sulfonylureas. According to the results of this review, the AGS Beers Criteria® are actively used in healthcare practice in Russia and abroad to reduce the undesirable effects of potentially inappropriate medication use in elderly patients by optimising the selection of medicines and treatment regimens; to train healthcare providers and patients in the principles of rational pharmacotherapy; to reduce the cost of pharmacotherapy; and to assess the quality of medical care.CONCLUSIONS. The AGS Beers Criteria® are an effective tool for identifying potentially inappropriate medications in prescribed therapy and selecting appropriate alternatives. Their practical application in healthcare settings can reduce ADRs, hospital admissions, and mortality rates in elderly and senile patients.

INTRODUCTION. The risk of liver damage correlates with the severity of COVID-19. However, a growing number of studies have shown an association between liver function impairment and combinations of medicinal products used to treat COVID-19.AIM. The study aimed to analyse the annual consumption of medicinal products associated with a high risk of drug-induced liver injury (DILI) used as part of combination therapy in COVID-19 patients and to review a number of medication administration records in order to develop measures to prevent DILI.MATERIALS AND METHODS. The study used the ATC/DDD methodology to study consumption data for 2020, 2021, and 2022 and analysed a sample of 1250 inpatient medical records and medication administration records of COVID-19 patients treated in a Volgograd region hospital converted into a COVID-19 care centre. For genetically engineered biologicals and cyclophosphamide, which were lacking DDDs, the authors calculated the volume of consumption using the average dose per treatment course. The authors identified medicines capable of causing clinically apparent liver damage (according to the LiverTox database and Russian clinical practice guidelines) and/or elevated liver enzymes in ≥1% of patients (according to safety reports).RESULTS. The study found that 28% of the medicinal products used in combination for inpatient treatment of COVID-19 were associated with a high risk of DILI. In 2020, 2021, and 2022, the total consumption of medicinal products associated with a high risk of DILI was 342.3, 425.3, and 402.3 DDDs per 100 bed days, and the total consumption of genetically engineered biologicals (administered as a single dose) and cyclophosphamide was 3.5, 16.9, and 29.7 average course doses per 100 patients, respectively. According to the selective analysis of medical records, 19.8% (247/1250) reported concomitant use of 5 or more medicinal products associated with a high risk of DILI, which increased the risk of adverse drug interactions leading to DILI. In 2022, the most prescribed medicinal products with a high risk of DILI were omeprazole (188.7 DDDs per 100 bed days), non-steroidal anti-inflammatory drugs and paracetamol (54.4 DDDs per 100 bed days), atorvastatin (46.2 DDDs per 100 bed days), levofloxacin (26.4 DDDs per 100 bed days), ceftriaxone (20.5 DDDs per 100 bed days), favipiravir (17.3 DDDs per 100 bed days), and genetically engineered biologicals (24.0 DDDs per 100 bed days).CONCLUSIONS. To reduce the risk of DILI in COVID-19 patients admitted to infectious disease units, including the risk of DILI due to drug interactions, it is necessary to limit the use of hepatotoxic antibacterial agents, proton-pump inhibitors, and non-steroidal anti-inflammatory drugs, or consider alternative medicinal products with a lower risk of hepatotoxicity.

INTRODUCTION. Methotrexate (MTX) is the main disease-modifying antirheumatic drug (DMARD) and the gold standard for the safety and efficacy evaluation of biologicals and targeted small molecules. However, its narrow therapeutic range, interpatient variability in pharmacokinetics and pharmacodynamics, and potential clinically relevant drug–drug interactions (DDIs) may lead to treatment failure and increase the risk of adverse drug reactions (ADRs).AIM. The study aimed to describe the main clinically significant DDIs associated with MTX used in rheumatic disease therapy and determine possible approaches to addressing this issue based on a literature review.DISCUSSION. MTX is characterised by pharmacokinetic DDIs during absorption, cell penetration, and elimination. Some non-steroidal anti-inflammatory drugs (NSAIDs), theophylline, sulfasalazine, antibacterial agents, and proton pump inhibitors (PPIs) affect MTX elimination and therapeutic effects. The main ADRs associated with MTX include haematotoxicity, hepatotoxicity, lung tissue damage (interstitial pneumonitis and pulmonary fibrosis), and renal dysfunction. The severity of these ADRs depends on the dose, comorbidities, and concomitant therapy. The toxicity of MTX may be increased by the concomitant administration of medicinal products that exhibit haematotoxicity and affect renal function (impair the elimination of medicines). When co-administering MTX and medicines having clinically significant DDIs described in the literature, healthcare providers should consider the risk factors for each individual patient. The most significant risk factors include moderate to severe renal and hepatic impairment, older age, polypharmacy, and hypoalbuminemia.CONCLUSIONS. This article describes potential clinically significant interactions between MTX and certain NSAIDs, antibacterial agents, and PPIs that depend on individual patient characteristics and may increase the toxicity or decrease the effectiveness of MTX. MTX deprescribing, short-term withdrawal, and dosing optimisation may be considered as approaches to DDI risk mitigation.

Background: In the intricate landscape of healthcare amid the COVID-19 pandemic, the emergence of mucormycosis as a severe complication posed a significant challenge to primary healthcare. This study delved into the complexities of adverse drug reactions (ADRs) in COVID-19 patients with mucormycosis undergoing treatment with conventional amphotericin B. Methods: Ethically approved and meticulously conducted, the study scrutinized 154 ADRs in depth, shedding light on their classification, outcomes, and interventions in COVID patients with mucormycosis. A descriptive analysis was carried out to report the findings of this study. Results: The findings revealed that a substantial proportion (85.6%) of these ADRs were manageable, emphasizing the need for vigilant monitoring and timely interventions. Notably, gender disparities surfaced, indicating potential gender-specific responses to amphotericin B. Causality assessments based on the WHO-UMC scale classified the majority of ADRs as certain, providing a robust foundation for understanding the intricate relationships between amphotericin B and the observed adverse events. Conclusion: This research not only categorizes ADRs as preventable and manageable but also offers practical insights into their nature and the diverse strategies employed for their management. The study’s outcomes underline the importance of personalized healthcare approaches that can be adopted by primary care physicians for effective patient care.

Background Currently, the treatment of refractory epilepsy (RE) in children is still a difficult point in epilepsy treatment. In China, pirenzapine (PER) is still a new drug for treating RE in children, and there is currently a lack of recommendations for adding PER to the treatment of RE in children. And in Chinese reports, the sample size of RE patients treated with PER is relatively small. Therefore, the efficacy of PER for pediatric RE, especially for young children with RE, still needs to be further studied with a large sample size. Objective To explore the efficacy, possible indications, adverse reactions, and tolerability of PER addition therapy for RE in children. Methods A self-control and retrospective analysis was conducted on children with RE aged 0-18 who were treated at the Women and Children's Hospital, Qingdao University from January 2022 to January 2023. The frequency of seizures at different observation points before and after the addition of PER treatment was compared, and the effective rate of PER was evaluated. Adverse drug reactions and drug retention rates were recorded, and the clinical characteristics of the effective and ineffective groups of PER were analyzed. Results A total of 192 study subjects were included. After adding PER treatment, the effective rates at 12, 24, and 36 weeks were 56.3% (108/192), 62.1% (113/182), and 69.7% (122/175), respectively, and the seizure free rates were 19.3% (37/192), 21.4% (39/182), and 24.6% (43/175). The incidence of adverse reactions was 16.1% (31/192), mainly including dizziness, irritability, weakness, and drowsiness. The last follow-up drug retention rate was 91.1% (175/192). There was a statistically significant difference in the onset age, duration of anti-epileptic treatment, type of origin, seizure form, frequency of seizures before the addition of PER, number of combined anti-epileptic drugs (ASMs), and ketogenic diet/surgical treatment between patients with RE who received continuous medication for 12 weeks (P

Aim: The aim of this study was to monitor prescription patterns, clinical outcomes, and adverse drug reactions (ADR) among patients of various interstitial lung diseases (ILDs). Materials and Methods: This prospective study was conducted in the Department of Pharmacology and Therapeutics in collaboration with the Department of Respiratory Medicine, King George’s Medical University, Lucknow, for a period of 12 months (October 2020–September 2021). A total of 77 patients were enrolled after satisfying the inclusion and exclusion criteria. The prescriptions were collected, and necessary details were noted on the case report form. After completion of the study, the data were analyzed for prescription patterns, clinical outcomes, and quality of life with the help of a validated questionnaire-King’s Brief ILD (KBILD) questionnaire. At the same time, ADRs, if any, were assessed using Hartwig’s Severity Assessment Scale and Naranjo Causality Assessment Scale. Results: The most common ILD was acute/chronic hypersensitivity pneumonitis (HP). Average number of drugs per encounter was 4.45. Crepitations were the most common clinical signs. Clubbing and rhonchi were reported maximum in idiopathic pulmonary fibrosis. It was found that psychological, breathlessness and activities, chest symptoms, and total KBILD reduced significantly after 3 months as compared to baseline with a statistically significant difference as P < 0.01. ADRs were found in 23.38% (18) of the subjects. Maximum ADR reported was gastritis (9.09%), followed by hepatitis (3.90%). Conclusion: The high proportion of patients clinically diagnosed with HP in our study highlights the importance of a detailed environmental exposure history in the diagnostic evaluation of patients with ILD to avoid inaccurate diagnoses. ADR-related hospital admissions are a significant problem in the health-care system.

Introduction: Type 2 diabetes mellitus (T2DM) is a common disease burdened with significant morbidity and mortality. Despite the substantial number of new available drug treatments, adherence to therapy and adverse drug reactions (ADRs) are the major constraint in the management of this disease. We evaluated the use, the adherence, and the safety of antidiabetic drugs in patients with T2DM. Methods: We performed an observational, retrospective, multicenter study on medical records of outpatients referred to general practitioners in Catanzaro (Calabria, Italy). Drug adherence was measured considering the packages of antidiabetic drugs prescribed at the time of admission, after three months, and 1 year later. ADRs were evaluated using the Naranjo probability scale. Collected data were analyzed using the Statistical Package for the Social Sciences. Results: During the study, we evaluated 12,170 medical records of seven general practitioners. The most prescribed drug was metformin alone (28.4%) or with other oral antidiabetics (19.6%) and then insulin (n: 354; men 190, women 164). Logistic regression showed an association between T2DM less than or equal to 5 years and low adherence (p = 0.023). During the study, we recorded 26 ADRs that were correlated with sex (women) and insulin treatment. Conclusions: this real-life study shows that patients with T2DM have a high adherence, probably related to their having a low number of ADRs.

Abstract Background Drug-drug interactions (DDIs) increase the incidence of adverse drug reactions (ADRs). In a previous report, we revealed that the incidence of potential DDIs due to the same CYP molecular species in one prescription exceeds 90% among patients taking six or more drugs and that CYP3A4 markedly influences the increase in the number of potential DDIs in clinical practice. However, the factors contributing to an increased number of potential DDIs in prescriptions from multiple clinical departments remain poorly clarified. Methods This observational study was performed at five pharmacies in Okayama Prefecture, Japan. Patients who visited these pharmacies from 11 April 2022 to 24 April 2022 were included, except those who had prescriptions only from a single clinical department. A stratified analysis was performed to determine the incidence of CYP3A4-related potential DDIs according to the number of drugs taken. Additionally, factors associated with an increase in the number of drugs involved in CYP3A4-related potential DDIs were identified using multiple linear regression analysis. In this study, potential DDIs for the prescription data subdivided by clinical department, containing two or more drugs, were used as control data. Results Overall, 372 outpatients who received prescriptions from multiple clinical departments were included in the current study. The number of drugs contributing to CYP3A4-related potential DDIs increased with an increase in the number of clinical departments. Notably, in cases taking fewer than six drugs, prescriptions from multiple clinical departments had a higher frequency of CYP3A4-related potential DDIs than those in prescriptions subdivided by clinical department. Multiple regression analysis identified "Cardiovascular agents", "Agents affecting central nervous system", and "Urogenital and anal organ agents" as the top three drug classes that increase CYP3A4-related potential DDIs. Conclusion Collectively, these results highlight the importance of a unified management strategy for prescribed drugs and continuous monitoring of ADRs in outpatients receiving prescriptions from multiple clinical departments even if the number of drugs taken is less than six.

Francis Kachidza Chiumia,1 Frider Chimimba,1 Happy Magwaza Nyirongo,1 Elizabeth Lusungu Kampira,2 Adamson Sinjani Muula,3 Felix Khuluza1 1Department of Pharmacy, School of Life Sciences and Allied Health Professions, Kamuzu University of Health Sciences, Blantyre, Malawi; 2Department of Medical Laboratory Sciences, School of Life Sciences and Allied Health Professions, Kamuzu University of Health Sciences, Blantyre, Malawi; 3Department of Community and Environmental Health, School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, MalawiCorrespondence: Felix Khuluza, Email fkhuluza@kuhes.ac.mwObjective: We aimed to assess the occurrence and characteristics of antibiotic-associated adverse drug reactions (ADRs) in Malawi.Methods: We retrospectively reviewed 304 patient records from medical wards in three hospitals in Southern Malawi. A global trigger tool was applied for the detection of suspected ADRs, and we used the Naranjo scale, the World Health Organization classification and the Schumock and Thornton scale for causality, seriousness and preventability assessment respectively. ADRs were also further characterized according to anatomical systems. Statistical analysis was done in STATA 14.1. The Chi-square test was used to determine the association between categorical variables and logistic regression analysis was used to measure the strength of the association between various independent variables and the occurrence of ADRs.Results: Suspected ADRs were detected in 24% (73/304) of patients, of which 1.4% were definite, 15.1% were probable and 83.6% were possible ADRs. Most of the sADRs were gastrointestinal events (42.5%), followed by: musculoskeletal (26.3%); cardiovascular (16.3%); central nervous system (13.8%; and urinary events (1.3%). About 27% of the sADRs were serious events such as convulsions. The geriatric age group (≥ 65 years) was more likely to experience sADRs as compared to the younger age group, with an adjusted odds ratio (aOR) of 4.53, 95% CI (2.21– 9.28), P< 0.001. Patients taking more than one antibiotic medicine had a higher risk of developing sADRs as compared to patients who were administered one type of antibiotic medicine, aOR 2.14, 95% CI (1.18– 3.90), p < 0.012. A long hospital stay of > 3days was associated with a higher risk of sADRs with aOR of 5.11, 95% CI (2.47– 10.55), p < 0.001 than those who stayed ≤ 3 days in the hospital.Conclusion: We found a higher prevalence of serious sADRs associated with antibiotic medicines than reported elsewhere. This may, among others, contribute to high patient mortality, poor treatment adherence, antibiotic resistance and increased cost of care.Plain Language Summary: What is already known and why we did the study?Most health care workers and patients are less likely to voluntarily report suspected adverse drug reactions in low- and middle-income countries such as Malawi.Studies have revealed a high usage of antibiotic medicines in Malawi, but there is limited data on the associated adverse drug reactions.What did we do?We assessed the occurrence and characteristics of ADRs associated with antibiotics.What are the new findings?We found a higher prevalence (24%) of adverse drug reactions associated with antibiotic therapy than reported elsewhere using the global trigger tool.About 27.4% of the events were serious ADRs such as convulsions, arrhythmia and hypotension.We observed a higher rate of convulsions which could be a potential safety signal.What do the new findings imply?The high prevalence of serious ADRs leads to complicated treatment strategies and contribute to patient mortality, poor treatment adherence and antibiotic resistance.ADR risk factors need to be considered when prescribing and monitoring patients on antibiotic therapy.Keywords: adverse drug reactions, antibiotic medicines, pharmacovigilance, global trigger tool, Malawi

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6; 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14; 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 ge­notype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous ge­notype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions ­associated with meropenem and tigecycline (r=9.8, p=0.002).CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Identification of the genetic features that determine a patient’s individual response to a medicinal product and provision of this information to a doctor helps to predict the effectiveness of therapy and the risk of adverse drug reactions. Dmitry A. Sychev — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Rector of the Russian Medical Academy of Continuous Professional Education — talks about the importance of a personalised approach to selecting medicinal products and methods for their efficacy and safety control.

INTRODUCTION. Osteoporosis is a leading cause of morbidity, disability, reduced quality of life, and premature mortality in the elderly population. Denosumab is a treatment for osteoporosis; however, denosumab discontinuation may cause a rebound effect, which is a severe adverse drug reaction (ADR) leading to an increase in the rate of bone tissue loss. Studying the mechanism of the rebound effect and potential ways to manage it can improve the safety of denosumab therapy.AIM. This study aimed to summarise up-to-date information regarding the mechanism of the rebound effect and ways to manage it after denosumab discontinuation.DISCUSSION. Osteoporosis results from an imbalance in bone remodelling. Recent studies have shown that mature osteoclasts are able to fission into osteomorphs, which separate from the polykaryon and fuse with neighbouring osteoclasts or other osteomorphs (osteoclast recycling). The mechanism of action of denosumab is based on the inhibition of osteoclast recycling, which results in the accumulation of pre-osteoclasts and osteomorphs. Research into processes occurring in bone tissue shows that denosumab creates a pool of induced cells, and when denosumab therapy is discontinued, these induced cells quite quickly and abundantly differentiate into osteoclasts causing bone resorption (rebound effect) and increasing the risk of fractures. In order to improve mineral bone density and to prevent fractures after denosumab discontinuation, it is reasonable to use antiresorptive medicines from the bisphosphonate class. Bisphosphonates accumulate in bone tissue and concentrate in areas of active bone metabolism.CONCLUSIONS. Further studies of the rebound effect mechanism, including a deeper understanding of the role of osteomorphs in osteogenesis, will improve the measures taken to reduce the risk of fractures after denosumab discontinuation. Further research is needed to evaluate the effect of antiresorptives on bone tissue loss after denosumab discontinuation.

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.