PLoS One. 2024 Jun 6;19(6):e0302287. doi: 10.1371/journal.pone.0302287. eCollection 2024.

ABSTRACT

BACKGROUND: The pharmacist plays an essential role in identifying and managing drug-related problems. The aim of this research was to assess the costs avoided by clinical pharmacist interventions to resolve drug-related problems.

RESEARCH DESIGN AND METHODS: Clinical pharmacists identified drug-related problems and interventions to address them in consecutive outpatients visiting internal medicine clinics at major teaching and public hospitals in Jordan from September 2012 to December 2013. The costs avoided by each intervention to address drug-related problems were collected from the literature. The collected data were used to calculate the overall cost saved and avoided by the interventions implemented to address the identified drug-related problems, adopting a Jordanian healthcare system perspective.

RESULTS: A total of 2747 patients were enrolled in the study. Diagnostic interventions, such as the need for additional diagnostic testing, were employed in 95.07% of the 13935 intervention to address the drug-related problem "Miscellaneous" which was the most frequent drug-related problems. Other common drug-related problems categories included inappropriate knowledge (n = 6972), inappropriate adherence (4447), efficacy-related drug-related problem (3395) and unnecessary drug therapy (1082). The total cost avoided over the research period was JOD 1418720 per month and total cost saved over the study period was JOD 17250.204. Drug-related problems were associated the number of prescription medications (odds ratio = 1.105; 95% confidence interval = 1.069-1.142), prescribed gastrointestinal drugs (3.485; 2.86-4.247), prescribed antimicrobials (3.326; 1.084-10.205), and prescribed musculoskeletal drugs (1.385; 1.011-1.852).

CONCLUSIONS: The study revealed that pharmacists have provided cognitive input to rationalize and optimize the medication use and prevent errors, that led to the reported projected avoided and saved expenditures via various interventions to address drug-related problems. This highlights the added economic impact to the clinical impact of drug-related problems on patients and the healthcare system. The high prevalence and cost of drug-related problems offer strong rationale for pharmacists to provide more vigilant intervention to improve patient outcomes while maintaining cost effectiveness.

PMID:38843244 | DOI:10.1371/journal.pone.0302287

J Med Internet Res. 2024 Jun 6;26:e50274. doi: 10.2196/50274.

ABSTRACT

Adverse drug reactions are a common cause of morbidity in health care. The US Food and Drug Administration (FDA) evaluates individual case safety reports of adverse events (AEs) after submission to the FDA Adverse Event Reporting System as part of its surveillance activities. Over the past decade, the FDA has explored the application of artificial intelligence (AI) to evaluate these reports to improve the efficiency and scientific rigor of the process. However, a gap remains between AI algorithm development and deployment. This viewpoint aims to describe the lessons learned from our experience and research needed to address both general issues in case-based reasoning using AI and specific needs for individual case safety report assessment. Beginning with the recognition that the trustworthiness of the AI algorithm is the main determinant of its acceptance by human experts, we apply the Diffusion of Innovations theory to help explain why certain algorithms for evaluating AEs at the FDA were accepted by safety reviewers and others were not. This analysis reveals that the process by which clinicians decide from case reports whether a drug is likely to cause an AE is not well defined beyond general principles. This makes the development of high performing, transparent, and explainable AI algorithms challenging, leading to a lack of trust by the safety reviewers. Even accounting for the introduction of large language models, the pharmacovigilance community needs an improved understanding of causal inference and of the cognitive framework for determining the causal relationship between a drug and an AE. We describe specific future research directions that underpin facilitating implementation and trust in AI for drug safety applications, including improved methods for measuring and controlling of algorithmic uncertainty, computational reproducibility, and clear articulation of a cognitive framework for causal inference in case-based reasoning.

PMID:38842929 | DOI:10.2196/50274

Infection. 2024 Jun 6. doi: 10.1007/s15010-024-02248-3. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore adverse event (AE) signals of Ceftazidime/avibactam (CZA) based on the FDA Adverse Event Reporting System (FAERS) database.

METHODS: AE reports primarily associated with CZA were retrieved from the FAERS database from the second quarter of 2015 to the second quarter of 2023. Signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) methods.

RESULTS: A total of 750 AEs reports with CZA as the preferred suspected drug were obtained, identifying 66 preferred terms (PTs) involving 24 system organ classes (SOCs). Besides, the AEs already mentioned in the drug label, this study also revealed some new, clinically valuable potential AEsignals, such as Cholestasis (n = 14, ROR 29.39, PRR 29.15, IC 3.34, EBGM 29.11), Drug-induced liver injury (n = 8, ROR 9.05, PRR 9.01, IC 2.25, EBGM 9.01), Hepatocellular injury (n = 7, ROR 13.90, PRR 13.84, IC 2.41, EBGM 13.63), Haemolytic anaemia (n = 5, ROR 24.29, PRR 24.22, IC 2.42, EBGM 40.53), etc. Additionally, AE signals with higher intensity were identified, such as Hypernatraemia (n = 5, ROR 40.73, PRR 40.61, IC 2.31, EBGM 24.19), Toxic epidermal necrolysis (n = 4, ROR 11.58, PRR 11.55, IC 1.89, EBGM 11.54). Therefore, special vigilance for these potential AEs is warranted when using CZA clinically.

CONCLUSION: This study highlights the potential AEs and risks associated with the clinical use of CZA, particularly the risks related to Cholestasis, Drug-induced liver injury, Haemolytic anaemia, Hypernatraemia, and Toxic epidermal necrolysis.

PMID:38842750 | DOI:10.1007/s15010-024-02248-3

Am J Dermatopathol. 2024 Jun 6. doi: 10.1097/DAD.0000000000002750. Online ahead of print.

ABSTRACT

Enfortumab is a monoclonal antibody directed against nectin-4 and, when combined with vedotin, is an antibody-drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancers. A 75-year-old woman with stage IV papillary urothelial carcinoma of the bladder who completed cycle 2 of enfortumab vedotin (EV) infusions presented to our dermatology department for new-onset symmetric and painful dusky erythematous patches on the extremities and trunk without mucosal involvement. Two biopsies were obtained, which revealed an interface dermatitis with notable ring mitoses within the basal and suprabasal layers of the epidermis without epidermal necrosis. The patient was diagnosed with toxic erythema of chemotherapy and improved with application of triamcinolone 0.1% ointment twice daily without discontinuation of her EV infusions. Although a targeted therapy, EV commonly exhibits cutaneous side effects due to the expression of nectin-4 in the skin. Most cutaneous side effects are mild and can be managed symptomatically. However, severe drug-induced eruptions, such as toxic epidermal necrolysis, have been described. The histologic findings of EV associated skin eruptions can aid in correctly identifying the culprit drug and assist in management. This case provides insights for dermatologists by highlighting the common cutaneous side effects of EV and the associated histologic findings as this targeted therapy becomes increasingly utilized in the treatment of refractory neoplasms.

PMID:38842397 | DOI:10.1097/DAD.0000000000002750

Cureus. 2024 May 6;16(5):e59718. doi: 10.7759/cureus.59718. eCollection 2024 May.

ABSTRACT

Gliadel wafer implants (Eisai Inc., Woodcliff Lake, NJ, USA) have shown their efficacy in prolonging survival in patients with malignant gliomas. The safety of Gliadel wafers has also been reported; however, there is a certain risk of adverse events. We present a rare case of refractory cerebrospinal fluid (CSF) leakage with eosinophilic meningitis in a patient with glioblastoma who underwent tumor resection with Gliadel wafer implants. A 60-year-old man presented with a glioblastoma in the right temporal lobe. The patient underwent tumor resection with Gliadel wafer implants. During the postoperative course, the patient presented with intractable CSF leakage and the development of a pseudomeningocele. A delayed rise in blood and CSF eosinophil count (a few weeks after the primary operation) and positive drug-induced lymphocyte stimulation test (DLST) results against the Gliadel wafer led to the diagnosis of an allergic reaction to these implants. Removal of the Gliadel wafers resolved the eosinophilic reaction; however, the patient subsequently required a shunt procedure for persistent hydrocephalus. This case highlights the importance of investigating rare causes of refractory CSF leakage and hydrocephalus due to allergic reactions to Gliadel wafers. Delayed elevations of eosinophils in blood and CSF tests may lead to a diagnosis of eosinophilic meningitis. DLST against Gliadel wafers is also useful for diagnosis when it is available. To control the hydrocephalus, not only the shunt procedure but also wafer removal must be considered; however, patients with limited life expectancy are generally hesitant to undergo such additional procedures.

PMID:38841004 | PMC:PMC11151347 | DOI:10.7759/cureus.59718

Drug Ther Bull. 2024 Jun 5:dtb-2024-000037. doi: 10.1136/dtb.2024.000037. Online ahead of print.

NO ABSTRACT

PMID:38839266 | DOI:10.1136/dtb.2024.000037

Drug Ther Bull. 2024 Jun 5:dtb-2024-000036. doi: 10.1136/dtb.2024.000036. Online ahead of print.

NO ABSTRACT

PMID:38839265 | DOI:10.1136/dtb.2024.000036

Ment Health Clin. 2024 Jun 3;14(3):204-211. doi: 10.9740/mhc.2024.06.204. eCollection 2024 Jun.

ABSTRACT

INTRODUCTION: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated.

METHODS: A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient's cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring.

RESULTS: Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal.

DISCUSSION: Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

PMID:38835819 | PMC:PMC11147652 | DOI:10.9740/mhc.2024.06.204

BMC Psychiatry. 2024 Jun 4;24(1):417. doi: 10.1186/s12888-024-05872-3.

ABSTRACT

BACKGROUND: Polypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders.

METHODS: The online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts' opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert's judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0.

RESULTS: After three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary "pharmacodynamic indicator" included "severity of adverse drug reactions", "duration of adverse drug reaction", "symptom relief", "time to onset of symptomatic relief", "number of days in hospital", and "duration of medication". The secondary "pharmacokinetic indicator" contained "dosage administered" and "dosing intervals". The primary "patient tolerance indicator" contained one secondary indicator of "patient tolerability". The primary indicator "patient adherence" contained one secondary indicator of "patient adherence to medication". The primary indicator "cost of drug combination" contained one secondary indicator of "readmission". These indicators were used to determine the clinical significance of DDIs during polypharmacy.

CONCLUSIONS: The clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders.

PMID:38834965 | DOI:10.1186/s12888-024-05872-3

Eur J Hosp Pharm. 2024 Jun 4:ejhpharm-2023-004073. doi: 10.1136/ejhpharm-2023-004073. Online ahead of print.

ABSTRACT

OBJECTIVES: Vancomycin, a glycopeptide antibiotic has antibacterial activity against Gram-positive bacteria and is frequently used in the intensive care unit (ICU). Inappropriate therapeutic drug monitoring (TDM) of vancomycin is a common problem encountered in hospital daily practice. The aim of this study was to evaluate the appropriateness of vancomycin trough-guided TDM in patients treated in the ICU using a clinical pharmacy approach.

METHODS: The study was conducted retrospectively in patients over 18 years old who had at least one vancomycin trough level and who had received intravenous (IV) vancomycin for ≥3 days between 1 November 2020 and 1 April 2022. The study included 137 patients. Patient demographics and relevant vancomycin TDM data were collected from medical records. The appropriateness of TDM was evaluated according to the criteria established based on the monitoring recommendations specified in consensus guidelines for therapeutic drug monitoring of vancomycin published by the American Society of Health-System Pharmacists (ASHP) in 2009 and 2020.

RESULTS: Of a total of 238 vancomycin trough levels measured in patients, 32.4% were collected at an inappropriate time. When patients were evaluated in terms of TDM appropriateness according to vancomycin level ranges (<10 µg/mL, 10-20 µg/mL and >20 µg/mL), we found the appropriate TDM was significantly higher in the therapeutic range (10-20 µg/mL) (p <0.001). Of the total 238 vancomycin trough concentrations taken from patients, 77 (32.4%) were measured at an inappropriate time. This caused dose withholding, wrong adjustments and therapy failure. The total TDM appropriateness of vancomycin was significantly higher in the therapeutic range defined as 10-20 µg/mL when evaluated based on 'TDM appropriateness criteria' (p <0.001).

CONCLUSION: Our study shows that appropriate vancomycin TDM increases the likelihood of achieving target trough concentrations. Involvement of clinical pharmacists in TDM management may prevent the development of adverse reactions by ensuring appropriate sampling time and appropriate interpretation of vancomycin levels.

PMID:38834285 | DOI:10.1136/ejhpharm-2023-004073

Cancer Lett. 2024 Aug 1;596:216998. doi: 10.1016/j.canlet.2024.216998. Epub 2024 Jun 1.

ABSTRACT

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are rare but fatal, requiring systemic steroid use. Therefore, to examine the outcomes, incidence, timing, and risk factors of ICI-associated steroid-requiring severe irAEs, we conducted a nationwide, retrospective, cohort study utilizing the Korean Health Insurance and Review Assessment database. We identified 357,010 patients with lung cancer, bladder cancer, or skin melanoma, eligible for ICI reimbursement in Korea between January 2012 to June 2020. Steroid-requiring severe irAEs following ICI treatment or treatment-emergent AEs following cytotoxic chemotherapy were defined as moderate- or high-dose steroid administration for over 2 consecutive days, along with corresponding ICD-10 codes indicating affected organ systems. The ICI-exposed group (N = 10,118) was compared to a matched cohort of 55,436 ICI-unexposed patients treated with cytotoxic chemotherapy. Incidences of acute severe irAEs requiring moderate- and high-dose steroids were higher in the ICI-exposed group (1.95% and 6.42%, respectively). The ICI-exposed group also had a higher risk of developing delayed severe irAEs requiring moderate- and high-dose steroid use (3.89% and 7.39%). Male sex, high comorbidity index, or previously diagnosed autoimmune diseases were associated with an increased risk of severe irAEs. Notably, 27.4-38.8% of the patients experienced recurrent severe irAEs after re-challenge with ICIs following moderate- or high-dose steroid use, with the severity matching the initial episode. Steroid-requiring severe irAEs were significantly more prevalent among patients exposed to ICIs than among those treated with chemotherapy in acute and delayed periods.

PMID:38830470 | DOI:10.1016/j.canlet.2024.216998

Inflamm Bowel Dis. 2024 Jun 3:izae112. doi: 10.1093/ibd/izae112. Online ahead of print.

ABSTRACT

BACKGROUND: Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC.

METHODS: This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle.

RESULTS: We included 101 children with a mean age at diagnosis of 12.8 ± 2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations.

CONCLUSIONS: In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data.

PMID:38828483 | DOI:10.1093/ibd/izae112

Sultan Qaboos Univ Med J. 2024 May;24(2):216-220. doi: 10.18295/squmj.1.2024.003. Epub 2024 May 27.

ABSTRACT

OBJECTIVES: This study aimed to report any suspected adverse drug reactions (ADRs) experienced by all vaccinated staff and students in a tertiary teaching hospital following COVID-19 vaccination.

METHODS: This retrospective study was conducted during the COVID-19 vaccination campaign at Sultan Qaboos University and Hospital in Muscat, Oman, from August to September 2021. An online survey was generated and sent to all staff and students via email and text messages. An announcement was made on the hospital website with a link to the survey.

RESULTS: A total of 8,421 individuals reported being vaccinated at least once with a total of 11,468 doses administered from January to July 2021; 8,014 staff and students received the Pfizer-Biotech vaccine while 3,454 staff and students received the Oxford-AstraZeneca vaccine. The survey received a total of 3,275 responses (response rate = 38.8%). Of these, 741 individuals (22.6%) experienced an ADR after vaccination and 67.2% (n = 498) were females (P <0.001). The majority of the ADRs reported were fever and chills (19.7%) followed by localised pain and swelling at the injection site (18.8%). Other ADRs such as hair loss (0.5%) were reported, and one staff/student reported a clot in the right leg. Among the responders, 27.0% considered their ADRs as mild while 25.0% considered them as severe.

CONCLUSIONS: In the study cohort, mild symptoms of COVID-19 vaccines were reported. Females experienced more ADRs compared to males. Long-term observation of ADRs to the vaccines and follow-up monitoring should be done on subjects to preclude any unwanted effects.

PMID:38828249 | PMC:PMC11139364 | DOI:10.18295/squmj.1.2024.003

Biol Pharm Bull. 2024;47(6):1079-1086. doi: 10.1248/bpb.b24-00072.

ABSTRACT

Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.

PMID:38825461 | DOI:10.1248/bpb.b24-00072

Ann Thorac Surg. 2024 May 30:S0003-4975(24)00396-5. doi: 10.1016/j.athoracsur.2024.05.019. Online ahead of print.

ABSTRACT

BACKGROUND: Advances in intraoperative molecular imaging (IMI) may improve surgical outcomes when resecting tumors in the lung. A single-center trial was conducted using VGT-309, a cathepsin-targeted near-infrared (NIR) imaging agent that causes lung nodules to fluoresce during surgery. The endpoint of this Phase 2 study was to evaluate the frequency that IMI with VGT-309 resulted in a clinically significant event (CSE): localization of pulmonary nodules, discovery of unsuspected additional cancers, or identification of positive margins.

METHODS: Patients undergoing surgical resection for known or suspected cancer in the lung received VGT-309 (0.32 mg/kg) preoperatively. During surgery, localization and resection of the nodules were performed using standard surgical techniques. NIR imaging was then used to localize nodules, seek occult lesions, and assess resection margins. Efficacy was measured by the frequency of CSEs.

RESULTS: Of the 40 patients who underwent pulmonary resection with VGT-309, 17 (42.5%) had at least 1 CSE. NIR imaging identified lesions not found by standard surgical methods in 16 participants, additional cancers not found by pre-operative imaging in 1 patient, and margins within 5 mm of the closest staple line in 2 individuals. VGT-309 performance was tested across a broad range of tumor types and commercial NIR imaging systems. VGT-309 appeared safe, well-tolerated, with no infusion reactions, and no drug-related serious adverse events.

CONCLUSIONS: This Phase 2 study demonstrated the utility of IMI with VGT-309 in localizing pulmonary nodules, recognizing synchronous lesions, and identifying positive margins. A multi-institutional study will further evaluate the efficacy of VGT-309.

PMID:38823756 | DOI:10.1016/j.athoracsur.2024.05.019

Trials. 2024 May 31;25(1):353. doi: 10.1186/s13063-024-08186-7.

ABSTRACT

BACKGROUND: The SAVVY project aims to improve the analyses of adverse events (AEs) in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). This paper summarizes key features and conclusions from the various SAVVY papers.

METHODS: Summarizing several papers reporting theoretical investigations using simulations and an empirical study including randomized clinical trials from several sponsor organizations, biases from ignoring varying follow-up times or CEs are investigated. The bias of commonly used estimators of the absolute (incidence proportion and one minus Kaplan-Meier) and relative (risk and hazard ratio) AE risk is quantified. Furthermore, we provide a cursory assessment of how pertinent guidelines for the analysis of safety data deal with the features of varying follow-up time and CEs.

RESULTS: SAVVY finds that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard.

CONCLUSIONS: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. Whenever varying follow-up times and/or CEs are present in the assessment of AEs, SAVVY recommends using the Aalen-Johansen estimator (AJE) with an appropriate definition of CEs to quantify AE risk. There is an urgent need to improve pertinent clinical trial reporting guidelines for reporting AEs so that incidence proportions or one minus Kaplan-Meier estimators are finally replaced by the AJE with appropriate definition of CEs.

PMID:38822392 | DOI:10.1186/s13063-024-08186-7

Comput Biol Med. 2024 Jul;177:108642. doi: 10.1016/j.compbiomed.2024.108642. Epub 2024 May 27.

ABSTRACT

BACKGROUND: Drug-drug interaction events influence the effectiveness of drug combinations and can lead to unexpected side effects or exacerbate underlying diseases, jeopardizing patient prognosis. Most existing methods are restricted to predicting whether two drugs interact or the type of drug-drug interactions, while very few studies endeavor to predict the specific risk levels of side effects of drug combinations.

METHODS: In this study, we propose MathEagle, a novel approach to predict accurate risk levels of drug combinations based on multi-head attention and heterogeneous attribute graph learning. Initially, we model drugs and three distinct risk levels between drugs as a heterogeneous information graph. Subsequently, behavioral and chemical structure features of drugs are utilized by message passing neural networks and graph embedding algorithms, respectively. Ultimately, MathEagle employs heterogeneous graph convolution and multi-head attention mechanisms to learn efficient latent representations of drug nodes and estimates the risk levels of pairwise drugs in an end-to-end manner.

RESULTS: To assess the effectiveness and robustness of the model, five-fold cross-validation, ablation experiments, and case studies were conducted. MathEagle achieved an accuracy of 85.85 % and an AUC of 0.9701 on the drug risk level prediction task and is superior to all comparative models. The MathEagle predictor is freely accessible at http://120.77.11.78/MathEagle/.

CONCLUSIONS: The experimental results indicate that MathEagle can function as an effective tool for predicting accurate risk of drug combinations, aiding in guiding clinical medication, and enhancing patient outcomes.

PMID:38820777 | DOI:10.1016/j.compbiomed.2024.108642

Clin Ther. 2024 May 30:S0149-2918(24)00106-1. doi: 10.1016/j.clinthera.2024.04.014. Online ahead of print.

ABSTRACT

PURPOSE: With the prolongation of human life expectancy and the outbreak of COVID-19, antineoplastic agents, anti-infective drugs, and cardiovascular system drugs have been widely applied, resulting in a growing incidence of drug-induced liver injury (DILI) year by year. This study aimed to investigate signals, clinical characteristics, and risk factors in patients with liver injury.

METHODS: A retrospective analysis was conducted on inpatients clinically diagnosed with DILI from 2019 to 2021 in one tertiary hospital in mainland China. The hepatic biochemical indices, clinical manifestations and suspected drugs of the patients were counted. We determined causality assessed by the Roussel Uclaf Causality Assessment Method in patients that the biochemistry met the diagnostic criteria recommended by the International Serious Adverse Events Consortium and compared them with contemporaneous patients diagnosed as DILI but with hepatic biochemical abnormalities only to identify the injure types and risk factors for DILI.

FINDINGS: A total of 1167 patients from 2639 initial participants with DILI were included. According to the injured target cells, it can be divided into hepatocellular injury type 351 cases (30.08%), cholestatic injury type 97 cases (8.31%), mixed injury type 27 cases (2.31%), and biochemical abnormal only type 692 cases (59.30%). It involved 1738 cases of suspected drugs, 349 drugs, and the top 3 drug categories were antineoplastic agents, anti-infectives, and traditional Chinese medicines, with Cyclophosphamide, Atorvastatin, and Liuzasulfapyridine as the top 3 in order of ranking. The main symptoms of patients were darker urine, decreased appetite, and yellow sclera. The overall prognosis of patients with DILI was favorable, with 280 recovered cases (23.99%), 691 improved cases (59.21%), 189 not improved cases (16.20%), and 7 deaths (0.60%). There were significant differences in gender, age, malignancy, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyltransferase, albumin, international normalized ratio, and prognosis among patients with different injury types (P < 0.05). Multiple logistic regression analysis showed that female (odds ratio [OR] = 1.897, P < 0.001), alcohol use (OR = 1.905, P = 0.001), malignancy (OR = 0.417, P < 0.001), and pregnancy (OR = 0.201, P = 0.011) were independent factors influencing DILI.

IMPLICATIONS: For most patients with liver injury, the manifestations are mild elevation of liver biochemistry without other symptoms (biochemical abnormal only type). The rest of the patients are predominantly of the hepatocellular injury type. Female and alcohol abuse patients are the risk factors of DILI, reminding clinicians to strengthen education on safe drug use, give individualized treatment, and regularly monitor liver function indexes in the patients.

PMID:38821767 | DOI:10.1016/j.clinthera.2024.04.014

J Psychiatr Pract. 2024 May 1;30(3):172-180. doi: 10.1097/PRA.0000000000000784.

ABSTRACT

INTRODUCTION: Adult patients and clinicians are faced with several pharmacological options to manage attention-deficit/hyperactivity disorder (ADHD). If types or rates of adverse experiences vary among these options, these differences could inform the shared decision-making process.

METHODS: To discern differentiating evidence-based patterns of risk, we analyzed data from FDA package labels for drugs approved to treat adult ADHD and reports from the registration trials used to create these labels. Three analyses of adverse effects were conducted: placebo-corrected occurrence at rates of 1 in 5, 10, and 20 participants, association with discontinuation, and uniqueness of occurrence within the treatment options.

RESULTS: Among the 7 agents approved to treat adult ADHD, the number of types of side effects experienced during a mix of fixed and flexible-dose studies was greatest among the nonstimulant medications, but the stimulant medications had higher rates of occurrence of side effects. The minimum frequency at which all medications had adverse events was 1 in 10 participants. Overall discontinuation rates did not differ among the stimulant medications nor between stimulants and nonstimulants.

DISCUSSION: To our knowledge, this is the first study to compile and compare data from all FDA registration trials for medications approved to treat adult ADHD. This article describes a process by which readily available adverse event reporting data can be used as a tool to inform shared clinical decision-making. While differences in the methodology and outcome reporting of the trials included may limit generalizability, the number of individual patients included and the completeness of the discontinuation data can be used to inform discussions with patients about the relative likelihood of adverse experiences and other patient concerns.

PMID:38819241 | DOI:10.1097/PRA.0000000000000784

Drug Ther Bull. 2024 May 30:dtb-2024-000035. doi: 10.1136/dtb.2024.000035. Online ahead of print.

NO ABSTRACT

PMID:38816185 | DOI:10.1136/dtb.2024.000035