Development and validation of a medication-based risk prediction model for acute kidney injury in older outpatients.

BACKGROUND: Older adults are at an increased risk of acute kidney injury (AKI), particularly in community settings, often due to medications. Effective prevention hinges on identifying high-risk patients, yet existing models for predicting AKI risk in older outpatients are scarce, particularly those incorporating medication variables. We aimed to develop an AKI risk prediction model that included medication-related variables for older outpatients. METHODS: We constructed a cohort of 2,272,257 outpatients aged ≥65 years using a national claims database. This cohort was split into a development (70%) and validation (30%) groups. Our primary goal was to identify newly diagnosed AKI within one month of cohort entry in an outpatient context. We screened 170 variables and developed a risk prediction model using logistic regression. RESULTS: The final model integrated 12 variables: 2 demographic, 4 comorbid, and 6 medication-related. It showed good performance with acceptable calibration. In the validation cohort, the area under the receiver operating characteristic curve value was 0.720 (95% confidence interval, 0.692-0.748). Sensitivity and specificity were 69.9% and 61.9%, respectively. Notably, the model identified high-risk patients as having a 27-fold increased AKI risk compared with low-risk individuals. CONCLUSION: We have developed a new AKI risk prediction model for older outpatients, incorporating critical medication-related variables with good discrimination. This tool may be useful in identifying and targeting patients who may require interventions to prevent AKI in an outpatient setting.

Development of a claims-based risk-scoring model to predict emergency department visits in older patients receiving anti-neoplastic therapy.

This study developed and validated a risk-scoring model, with a particular emphasis on medication-related factors, to predict emergency department (ED) visits among older Korean adults (aged 65 and older) undergoing anti-neoplastic therapy. Utilizing national claims data, we constructed two cohorts: the development cohort (2016-2018) with 34,642 patients and validation cohort (2019) with 10,902 patients. The model included a comprehensive set of predictors: demographics, cancer type, comorbid conditions, ED visit history, and medication use variables. We employed the least absolute shrinkage and selection operator (LASSO) regression to refine and select the most relevant predictors. Out of 120 predictor variables, 12 were integral to the final model, including seven related to medication use. The model demonstrated acceptable predictive performance in the validation cohort with a C-statistic of 0.76 (95% CI 0.74-0.77), indicating reasonable calibration. This risk-scoring model, after further clinical validation, has the potential to assist healthcare providers in the effective management and care of older patients receiving anti-neoplastic therapy.

Derivation and validation of a risk prediction score for nonsteroidal anti-inflammatory drug-related serious gastrointestinal complications in the elderly.

AIMS: Few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score for severe GI complications to identify high-risk elderly patients using NSAID. METHODS: We used the following two Korean claims datasets: customized data with an enrolment period 2016-2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥65 years) who received NSAIDs for more than 30 days. Serious GI complications were defined as hospitalizations or emergency department visits, with a main diagnosis of GI bleeding or perforation. We applied the logistic least absolute shrinkage and selection operator (LASSO) regression model for variable selection and model fitting. RESULTS: We identified 8176 cases and 81 760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254 551 patients. The risk predictors were high-dose NSAIDs, nonselective NSAID, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease and cirrhosis. Area under the receiver operating characteristic curve was 0.79 (95% confidence interval, 0.77-0.81) in the external validation dataset. CONCLUSIONS: The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.

Prevalence and predictors of medication-related emergency department visit in older adults: A multicenter study linking national claim database and hospital medical records.

Objectives: Older adults are more likely to experience drug-related problems (DRP), which could lead to medication-related emergency department visits (MRED). To properly evaluate MRED, the entire history of drug use should be evaluated in a structured manner. However, limited studies have identified MRED with complete prescription records. We aimed to evaluate the prevalence and risk factors of MRED among community-dwelling older patients by linking national claims data and electronic medical records using a standardized medication related admission identification method. Methods: We included older patients who visited the emergency departments of four participating hospitals in 2019. Among the 54,034 emergency department (ED) visitors, we randomly selected 6,000 patients and structurally reviewed their medical records using a standardized MRED identification method after linking national claims data and electronic medical records. We defined and categorized MRED as ED visits associated with adverse drug events and those caused by the underuse of medication, including treatment omission and noncompliance and assessed as having probable or higher causality. We assessed preventability using Schumock and Thornton criteria. Results: MRED was observed in 14.3% of ED visits, of which 76% were preventable. In addition, 32.5% of MRED cases were related to underuse or noncompliance, and the rest were related to adverse drug events. Use of antipsychotics, benzodiazepines, anticoagulants, traditional nonsteroidal anti-inflammatory drugs without the use of proton pump inhibitors, P2Y12 inhibitors, insulin, diuretics, and multiple strong anticholinergic drugs were identified as predictors of MRED. Conclusion: One in seven cases of ED visits by older adults were medication related and over three-quarters of them were preventable. These findings suggest that DRPs need to be systemically screened and intervened in older adults who visit ED.

Rebamipide as a Potential Alternative Gastroprotective Agent to Proton Pump Inhibitor in Elderly Chronic Nonsteroidal Anti-Inflammatory Drug Users without Risk Factors.

Purpose: The use of proton pump inhibitors (PPI) is recommended to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complications. The incidence of several adverse effects during the long-term use of PPI prompts the search for other alternatives. Limited studies have evaluated the efficacy of rebamipide, a widely used mucoprotective drug, as a gastroprotective agent (GPA) compared to PPI, focusing on the elderly chronic NSAID users, nor with GI risk stratification. We aimed to determine the population who would get benefit from the use of rebamipide as an alternative to PPI to prevent traditional nonsteroidal anti-inflammatory drug (tNSAID)-associated GI complications. Patients and Methods: We identified 41,889 and 35,708 elderly chronic tNSAID users with PPI and rebamipide co-therapy, respectively, from the national claims database. Outcome was defined as hospitalization or emergency department visits due to serious GI complications. Propensity score-matched cohorts were constructed and compared within risk strata. Results: In high and moderate risk groups with two risk factors, rebamipide showed a higher risk of serious GI complication compared to PPI (aHR 2.63, 95% CI 1.24-5.59 and aHR 2.42, 95% CI 1.21-4.83, respectively). However, in elderly patients without risk factors, there was no significant difference in the risk of serious GI complications between PPI and rebamipide (aHR 0.69, 95% CI 0.27-1.76). Conclusion: This study suggested that rebamipide can be considered as an alternative to PPI in elderly chronic tNSAID users without risk factors. However, elderly patients with other risk factors should use PPI rather than rebamipide. Therefore, the presence of GI risk factors needs to be evaluated in elderly chronic tNSAID users to prescribe the most suitable GPA in clinical practice.

Impact of Preventive Strategies on Gastrointestinal Complications in Elderly Patients on Concomitant Use of Oral Anticoagulants and Nonsteroidal Anti-Inflammatory Drugs: A Nationwide Cohort Study.

INTRODUCTION: Despite growing evidence showing an increased risk of concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants, few studies have investigated whether proton pump inhibitors can prevent gastrointestinal (GI) complications in patients receiving both NSAIDs and anticoagulants. OBJECTIVE: We aimed to evaluate the risk of serious GI complications and the impact of GI preventive strategies on the concomitant use of NSAIDs and anticoagulants. METHODS: Our nationwide cohort study using Korea's claims data included elderly patients (aged ≥ 65 years) who started anticoagulants and NSAIDs from 2016 to 2017. The outcome was serious GI complications defined as hospitalization or emergency department visits with GI bleeding or perforation. A Cox regression analysis was performed using time-dependent variables and propensity score matching. RESULTS: In total, 92,379 patients were identified. Compared with non-prophylaxis, proton pump inhibitors and selective cyclooxygenase-2 inhibitors were associated with a 64% [adjusted hazard ratio, 0.36 (95% confidence interval 0.25-0.53)] and 74% [adjusted hazard ratio, 0.26 (95% confidence interval 0.19-0.36)] lower risk of serious GI complications, respectively. Cyclooxygenase-2 inhibitor use was not different from the use of non-selective NSAIDs with proton pump inhibitors for the prevention of serious GI complications. H2-receptor antagonists did not reduce the risk of serious GI complications compared with non-prophylaxis during concomitant non-selective NSAID and anticoagulant therapy. CONCLUSIONS: Proton pump inhibitors or cyclooxygenase-2 inhibitors used as GI preventive strategies did not completely eliminate but lowered the risk of serious GI complications among elderly patients receiving both NSAIDs and anticoagulants.

Single enzyme nanoparticle, an effective tool for enzyme replacement therapy.

The term "single enzyme nanoparticle" (SEN) refers to a chemically or biologically engineered single enzyme molecule. SENs are distinguished from conventional protein nanoparticles in that they can maintain their individual structure and enzymatic activity following modification. Furthermore, SENs exhibit enhanced properties as biopharmaceuticals, such as reduced antigenicity, and increased stability and targetability, which are attributed to the introduction of specific moieties, such as poly(ethylene glycol), carbohydrates, and antibodies. Enzyme replacement therapy (ERT) is a crucial therapeutic option for controlling enzyme-deficiency-related disorders. However, the unfavorable properties of enzymes, including immunogenicity, lack of targetability, and instability, can undermine the clinical significance of ERT. As shown in the cases of Adagen®, Revcovi®, Palynziq®, and Strensiq®, SEN can be an effective technology for overcoming these obstacles. Based on these four licensed products, we expect that additional SENs will be introduced for ERT in the near future. In this article, we review the concepts and features of SENs, as well as their preparation methods. Additionally, we summarize different types of enzyme deficiency disorders and the corresponding therapeutic enzymes. Finally, we focus on the current status of SENs in ERT by reviewing FDA-approved products.

Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery.

A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with <75nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy. STATEMENT OF SIGNIFICANCE: Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.

Determination and validation of psammaplin A and its derivatives in rat plasma by liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic study.

A liquid chromatography-tandem mass (LC-MS/MS) method was developed for the determination of psammaplin A (PsA) and its newly synthesized derivatives (PsA 107, PsA 109, and PsA 123) in rat plasma using bupropion as an internal standard (IS). The plasma samples were deproteinized with acetonitrile. Chromatographic separation was performed on hydro-RP column (75×2.0mm, 80Å, 4µm) with isocratic elution using 5mM ammonium formate buffer/acetonitrile (30:70, v/v) at a flow rate of 0.4mL/min and the total run time was 5min. Mass spectrometric detection was performed with positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The ion transitions monitored were m/z 663.2→331.0, 687.2→343.1, 587.3→293.1, 563.3→281.0, and 240.0→184.0 for PsA, PsA 107, PsA 109, PsA 123, and IS, respectively. All analytes showed good linearity over the concentration range of 5.00-5000ng/mL (r(2)≥0.994). The lower limit of quantification was 5ng/mL for PsA and its three PsA derivatives. Within- and between-run precisions (relative standard deviation, RSD) were less than 9.66% and accuracy (relative error, RE) ranged from -9.34% to 7.25%. Established method was successfully applied to the investigation of pharmacokinetic properties of PsA and its derivatives in rats after intravenous administration at a dose of 2mg/kg.