Therapeutic Advances in Drug Safety最新文献

Background: Unlike the propofol-opioids combination, a single dose of S-ketamine with propofol achieves the same anesthetic effects while effectively minimizing adverse reactions in painless abortion. Ciprofol, a novel analog of propofol, has distinct advantages, its application in painless abortion is underexplored.

Objectives: To investigate a 90% effective dose (ED₉₀) of ciprofol and propofol with S-ketamine for painless abortion.

Design: This prospective biased coin up-and-down (BCUD) sequential dose-finding study aimed to estimate the ED₉₀ of ciprofol when administered with 0.15 mg/kg S-ketamine in painless abortion while comparing adverse effects incidence with the ED₉₀ of propofol when combined with the same dose of S-ketamine.

Methods: Eighty patients were recruited and randomly allocated to either ciprofol or propofol groups, with initial doses of 0.375 mg/kg and 1.5 mg/kg, respectively. The dose for the subsequent patient in the study was based on the response of the preceding patient, following the BCUD design. The study estimated the ED₉₀ using isotonic regression. Secondary outcomes, including the incidence of injection pain, vital signs, and adverse events, were recorded and compared between the two groups.

Results: The ED₉₀ of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg (95% confidence interval: 0.498-0.510), while the ED₉₀ of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg (95% confidence interval: 1.98-2.16). Patients in the ciprofol group had a lower incidence of respiratory pause (7.5% vs 52.5%; p < 0.001). Other adverse events and recovery time were comparable between groups.

Conclusion: Compared to propofol and S-ketamine combination, ciprofol and S-ketamine are equally effective with reduced respiratory depression. Thus, clinicians should consider a dose of 0.5 mg/kg ciprofol with 0.15 mg/kg S-ketamine for painless abortion.

Trial registration: http://www.chictr.org.cn; ChiCTR2400086522; July 5, 2024.

Background: The risk factors related to the adverse drug reactions (ADRs) of anlotinib have been rarely investigated. In addition, a corresponding risk prediction model has not been established in China pertaining to anlotinib-related ADRs.

Objectives: To manage ADRs more efficiently and improve the prognosis of patients administered anlotinib.

Design: A retrospective analysis was conducted using the medical records of patients diagnosed with cancer who were administered anlotinib after hospitalization between January 1, 2020, and December 31, 2023.

Methods: We performed a combination of univariate analysis and multivariate binary logistic regression analysis to identify significant factors that can accurately predict ADRs. Model fitting was performed using forward selection. The accuracy of the prediction model was expressed as the area under the receiver operating characteristic curve (AUC). The final ADR risk model was validated.

Results: In this study, 300 patients who were administered anlotinib were included. Among them, 238 (79.33%) patients experienced at least one ADR. Diagnosis, combination treatment, distant metastasis, treatment lines, and cumulative dose were independent risk factors for the ADRs of anlotinib. The AUC and the concordance index of the nomogram constructed from the above five factors were 0.790 and 0.789, respectively. The results of the Hosmer-Lemeshow test showed that the model was a good fit (p = 0.811). In addition, the decision curve analysis demonstrated a significantly higher net benefit of the model. The external validation indicated that the prediction nomogram was reliable.

Conclusion: We developed and validated a simple model to use the ADR risk score in patients who were administered anlotinib. This risk prediction model was well-calibrated and discriminative. It can be used as a reference for clinical decision-making. It has clinical significance for preventing ADRs, improving the prognosis of patients, and providing support for the rational use of drugs.

Local anesthetics have a broad application for minor and major surgeries, in outpatient and inpatient settings. Drug dosing, frequency, duration of action, and coadministration with other drugs, are some of many factors that must be considered for each patient, before drug administration. Like other medical treatments, the use of local anesthetics has potential complications, such as local anesthetic systemic toxicity (LAST). LAST primarily affects the cardiac and central nervous systems (CNS), seizures and cardiac arrest being some of the more time-sensitive symptoms requiring immediate treatment. Patients should be briefed on potential symptoms if LAST occurs and physicians should be aware of the warning signs, treatment, and prevention. In our case study, a 40-year-old, 51 kg woman was administered a lidocaine dosage of 760 mg in an outpatient setting. She presented to the emergency department with diffuse tremors, paresthesias of the mouth and face, spasticity, irritability, and a single generalized tonic-clonic seizure. The patient was successfully treated with Ativan along with lipid emulsion. We review this case and perform a literature review to identify key points in the use of local anesthetics. Healthcare providers should be trained in LAST treatment and prevention. Our case study therefore serves to reduce the frequency of LAST and other adverse outcomes associated with local anesthetic administration.

Background: Although there are reports of adverse events (AEs) of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, the safety of ribociclib alone has not yet been comprehensively evaluated in real-world clinical practice.

Objectives: To investigate the overall real-world safety profile of ribociclib by mining data from the FDA Adverse Event Reporting System (FAERS).

Design: A retrospective disproportionality analysis was conducted based on the FAERS database.

Methods: We processed reports from the first quarter of 2017 to the second quarter of 2023 and applied disproportionality analysis using four different methods: reporting odds ratio, Medicines and Healthcare Products Regulatory Agency, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker.

Results: A total of 12,885 AE reports of ribociclib as the primary suspect were enrolled. 48.81% of AEs occur within 60 days of ribociclib administration. Blood and lymphatic system disorders and abnormalities in investigation at the system organ class level showed statistically significant signals in all four methods. Nausea (n = 1426), neutropenia (n = 940), vomiting (n = 863), white blood cell count decreased (n = 812), and alopecia (n = 536) turned out to be the five most frequent AEs at the preferred term level. Twenty-eight AEs undiscovered in the label were newly identified. Neutropenia, as a widely recognized AE, was observed to potentially result in more serious outcomes than previously anticipated (p < 0.001).

Conclusion: This study utilized the FAERS database to analyze real-world AE signals associated with ribociclib following its market approval. We characterized the clinical profiles of reported AEs and found some significant signals consistent with previous clinical trials. In addition, several AEs not included in the drug label or exhibiting unexpected severity were detected. These findings provide valuable insights for clinicians and highlight directions for further causality-focused research to validate the observed results.

Artificial intelligence (AI) is transforming medication research and development, giving clinicians new treatment options. Over the past 30 years, machine learning, deep learning, and neural networks have revolutionized drug design, target identification, and clinical trial predictions. AI has boosted pharmaceutical R&D (research and development) by identifying new therapeutic targets, improving chemical designs, and predicting complicated protein structures. Furthermore, generative AI is accelerating the development and re-engineering of medicinal molecules to cater to both common and rare diseases. Although, to date, no AI-generated medicinal drug has been FDA-approved, HLX-0201 for fragile X syndrome and new molecules for idiopathic pulmonary fibrosis have entered clinical trials. However, AI models are generally considered "black boxes," making their conclusions challenging to understand and limiting the potential due to a lack of model transparency and algorithmic bias. Despite these obstacles, AI-driven drug discovery has substantially reduced development times and costs, expediting the process and financial risks of bringing new medicines to market. In the future, AI is expected to continue to impact pharmaceutical innovation positively, making life-saving drug discoveries faster, more efficient, and more widespread.

Background: The association between dipeptidyl peptidase-4 inhibitors (DPP-4i) exposure and the risk of colorectal cancer (CRC) in patients with type 2 diabetes mellitus (T2DM) is unclear.

Objectives: This meta-analysis aims to investigate the relationship between DPP-4i exposure and the incidence of CRC in patients with T2DM.

Design: A systematic review and meta-analysis.

Methods: A comprehensive search of electronic databases, including PubMed, Web of Science, EMBASE, and ScienceDirect, was conducted up to March 2024. The studies including randomized clinical trials (RCTs), cohort studies, and case-control studies were retrieved. The odds ratio (OR) was calculated using Stata 12.0 statistical software. The primary outcome assessed was the incidence of CRC.

Results: This meta-analysis incorporated six retrospective cohort studies and two case-control studies. The findings indicate that the incidence of CRC in the DPP-4i exposure group was significantly higher than that in the control group (OR = 1.11, 95% CI: 1.02-1.21, p = 0.013). Subgroup analysis revealed that both male (OR = 2.07, p < 0.001) and female participants (OR = 1.49, p = 0.05) in the DPP-4i exposure group exhibited a significantly higher incidence of CRC compared to the control group. Among participants younger than 65 years, the incidence of CRC was markedly elevated in the exposure group (OR = 2.81, p < 0.001). Furthermore, when the exposure duration was less than 1 year, the CRC incidence in the exposure group surpassed that of the control group (OR = 1.24, p = 0.005). When sulfonylureas (SU) were used as control drugs, the incidence of CRC was higher in the exposure group (OR = 1.10, p = 0.017).

Conclusion: There is a potential correlation between DPP-4i exposure and increased incidence of CRC in T2DM patients. This association appears to be influenced by gender, age, duration of exposure, and the choice of control medications. Therefore, attention should be paid to colorectal diseases when DPP-4i is employed in the clinic.

Trial registration: The meta-analysis has been registered with the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42024535292.

Background: Patients with low body weight (LBW) often exhibit altered pharmacokinetics (PK) in renal clearance and total body water. These changes complicate β-lactam antibiotic dosing, potentially resulting in suboptimal efficacy or increased toxicity.

Objectives: To evaluate the attainment of PK/pharmacodynamic (PD) targets, the prevalence of subtherapeutic and supratherapeutic concentrations, and the incidence of neurotoxicity among LBW patients treated with piperacillin/tazobactam (TZP), cefepime (FEP), and meropenem (MEM).

Design: A prospective observational study conducted at a tertiary hospital from January 2020 to December 2022.

Methods: Adult patients with a body mass index ⩽18.5 kg/m² who received TZP, FEP, or MEM were included. Trough serum concentrations were analyzed for PK/PD targets: 100% time above minimum inhibitory concentration (100% fT > MIC) and 100% time above four times MIC (100% fT > 4MIC). Neurotoxicity was assessed using standardized criteria. Statistical analyses identified factors associated with concentration variability and adverse outcomes.

Results: Seventy-two patients were included: 29 received TZP, 23 FEP, and 20 MEM. Achievement of the 100% fT > MIC target was comparable across all antibiotics (~70%), but 100% fT > 4 MIC attainment was significantly higher for FEP (47.8%) than for TZP (10.3%) and MEM (30%) (p = 0.01). Supratherapeutic concentrations were observed in 34.8% of FEP users compared to 3.4% and 5% for TZP and MEM, respectively (p = 0.002). Neurotoxicity occurred in 13% of FEP patients but was not reported in TZP or MEM groups (p = 0.04). Subtherapeutic concentrations were noted in approximately 30% of patients across all groups.

Conclusion: PK changes complicate β-lactam antibiotic dosing, resulting in frequent failure to achieve PK/PD targets. FEP demonstrated a particularly high risk of supratherapeutic concentrations and neurotoxicity. Therapeutic drug monitoring is crucial to optimize dosing and improve safety in this population.

Hospital pharmacies play a unique role in healthcare by regularly compounding drug products (DPs) in response to hospital demands and practices, for example, drug shortages, to cater to frail and vulnerable patients with infectious, chronic or nutrition-related conditions. Drugs are compounded in precise concentrations for extended durations, sometimes involving complex formulations. A significant challenge in this context is the off-label use of short-term plastic primary packaging for long-term storage of compounded DPs, which could be due to a lack of awareness, financial constraints and inadequate regulation. Without proper risk assessments, such packaging can release potentially harmful leachable compounds, posing a serious threat to patient safety. Evaluating hospital pharmacy compounding procedures to mitigate this risk is essential. While off-label drug use is a well-known concept in hospitals, off-label use of plastic primary packaging is an entirely different practice. In both the United States and Europe, healthcare professionals, including pharmacists, are allowed to use medical devices, including primary packaging, in ways that are not explicitly approved by regulators based on their clinical judgement and best practices, taking into account the patient's best interest. However, this off-label use could bring about unique risks and challenges, especially in the highly controlled environment of hospital pharmacy compounding, where patient safety is crucial. Therefore, the current review explores the historical context and the current landscape of hospital pharmacies, investigates the potential root causes of container closure integrity issues in pharmaceutical compounding, discusses the materials of construction as well as their physical-chemical properties influencing their roles in most popular primary packaging and finally presents expert opinions aimed at identifying long-term solutions to the existing challenges regarding their off-label uses in hospital pharmacy compounding.

Background: Current guidelines recommend the use of only on a limited basis in patients with normal or minimal structural heart disease. The CAST study, the only randomized controlled trials, showed increased mortality from long-term flecainide use in post-myocardial infarction (MI) patients with reduced left ventricular ejection fraction (LVEF). However, many later studies have revealed its safety when used in other structural heart diseases.

Objectives: This study investigates the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) VT/VF in patients with structural heart disease compared to those with a normal heart when using flecainide.

Methods: We retrospectively recruited patients who had received at least one dose of flecainide in the past 5 years. Baseline characteristics, indications for flecainide use, and echocardiography results were reviewed. After 1 year, we evaluated the incidence of ventricular arrhythmias and all-cause mortality.

Results: After screening, 447 patients had received at least one dose of flecainide, and 336 patients were included in the study. Forty-seven patients (14%) had structural heart disease as defined by our protocols. Left ventricular hypertrophy (LVH) and impaired LVEF accounted for 28% and 25% of cases, respectively. There were five patients with coronary artery disease (CAD). After 1 year, ventricular arrhythmias occurred in two patients (4.7%) in the structural heart group; these patients had also experienced arrhythmias before receiving flecainide. In the non-structural heart group, ventricular arrhythmias were detected in three patients (1.1%). In multivariate analysis, structural heart disease was not associated with an increased incidence of ventricular arrhythmias (OR = 4.8 (0.6-38.44), p = 0.139).

Conclusion: Our study showed that no patients died due to ventricular arrhythmia, and the incidence of VT/VF was not increased in patients with structural heart disease. A prospective study is needed to further evaluate the safety of flecainide in patients with structural heart disease other than ischemic heart disease.

In 2019, intranasal esketamine gained approval as a promising therapy for those individuals grappling with treatment-resistant depression. Both clinical trials and real-world studies have underscored its efficacy in alleviating and remitting depressive symptoms, with sustained benefits observed for nearly 4.5 years. As the S-enantiomer of ketamine, esketamine's dosing guidelines and strict medical supervision stem from prior research on ketamine's use in depression and history as a recreational drug. Despite initial concerns, long-term clinical studies have not documented instances of abuse, misuse, addiction or withdrawal, and the same was found in case reports or subsamples of high-risk populations with comorbidities such as substance use disorder or alcohol use disorder. Esketamine has proven to be safe and well tolerated without fostering new-onset substance use in vulnerable groups. Real-world studies reinforced these observations, reporting no adverse events (AEs) related to pharmacological interactions of esketamine with any other substance, and no new-onset drug or alcohol misuse, craving, misuse or diversion of use. Reports of esketamine craving remain rare, with only one case report documented in 2022. Most drug-related AEs reported in pharmacovigilance databases are those identified in the product's technical data sheet and with known reported frequency. More importantly, no register of illicit acquisition of esketamine or its tampering for obtaining ketamine or other altered products was found in our search. Overall, our review confirms esketamine's safety across diverse patient populations, reassuring its responsible use and the scarcity of reports of abuse or misuse since its introduction to the market.