Development of a Simple and Validated LC-MS/MS Method for Quantitative Determination of Ketotifen in Beagle Dog Plasma and Its Application to Bioequivalence Study of Ketotifen Syrup Dosage Form.

A highly accurate, precise, and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for ketotifen (KTF) estimation from Beagle dog plasma was developed and validated, with ketotifen-d3 (KTF-d3) as the internal standard (IS). KTF and IS were detected on an API 4000 mass spectrometer in multiple reaction monitoring (MRM) mode in electrospray ionization (ESI) positive ionization mode. The transitions were monitored at m/z 310.2 → 96.0 for KTF and m/z 313.2 → 99.1 for IS. KTF and IS were extracted from plasma using liquid-liquid extraction with methyl tertiary-butyl ether and then analyzed for 3 min with extracted samples (7 µL) into the LC-MS/MS system. Analytes were separated on a Luna® Hilic column (50 × 2.0 mm i.d., 3 µm) using the Nexera X2 HPLC. The mobile phase A consisted of 10 mmol/L ammonium formate (pH 3.0), while mobile phase B consisted of 0.05% formic acid in acetonitrile. The ratio of mobile phase was 5:95 (v/v) at a flow rate of 0.2 mL/min. The method has been thoroughly validated in accordance with the bioanalytical method validation guidelines established by the Ministry of Food and Drug Safety in Korea and the U.S. Food and Drug Administration, addressing selectivity, lower limit of quantification, linearity, carryover, precision, accuracy, recovery, matrix effect, and stability. The developed LC-MS/MS method was effectively utilized for the bioequivalence assessment of ketotifen in Beagle dog plasma following the oral administration of ketotifen syrup.

Real-World Data-Derived Pharmacovigilance on Drug-Induced Cognitive Impairment Utilizing a Nationwide Spontaneous Adverse Reporting System.

Background and Objectives: Despite high incidences of cognitive impairment with aging, evidence on the prevalence and the seriousness of drug-induced cognitive impairment is limited. This study aims to evaluate the prevalence and the severity of drug-induced cognitive impairment and to investigate the clinical predictors of increased hospitalization risk from serious drug-induced cognitive impairment. Materials and Methods: Adverse drug events (ADEs) regarding drug-induced cognitive impairment reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were included (KIDS KAERS DB 2212A0073). The association between the etiologic classes and the reporting serious adverse events (SAEs) was evaluated using disproportionality analysis, and the effect was estimated with reporting odds ratio (ROR). Clinical predictors associated with increased risk of hospitalization from SAEs were identified via multivariate logistic analysis, and the effect was estimated with odds ratio (OR). Results: The most etiologic medication class for drug-induced cognitive impairment ADEs was analgesics, followed by sedative-hypnotics. Anticancer (ROR 57.105, 95% CI 15.174-214.909) and anti-Parkinson agents (ROR 4.057, 95% CI 1.121-14.688) were more likely to report serious drug-induced cognitive impairments. Male sex (OR 19.540, 95% CI 2.440-156.647) and cancer diagnosis (OR 18.115, 95% CI 3.246-101.101) are the major clinical predictors for increased risk of hospitalizations due to serious drug-induced cognitive impairment. Conclusions: This study highlights the significant prevalence and severity of drug-induced cognitive impairment with cancer diagnosis and anticancer agents. However, further large-scaled studies are required because of the potential underreporting of drug-induced cognitive impairments in real practice settings, which is further contributed to by the complexity of multiple contributing factors such as comorbidities.

Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats.

This study aimed to establish a simple and sensitive analytical method to simultaneously quantify donepezil (DPZ) and tadalafil (TAD) in rat plasma using lansoprazole (LPZ) as an internal standard (IS) by using liquid chromatography tandem mass spectrometry. The fragmentation pattern of DPZ, TAD, and IS was elucidated using multiple reaction monitoring in electrospray ionization positive ion mode for the quantification of precursor to production at m/z 380.1 → 91.2 for DPZ, m/z 390.2 → 268.1 for TAD, and m/z 370.3 → 252.0 for LPZ. The extracted DPZ and TAD from plasma using acetonitrile-induced protein precipitation was separated using Kinetex C18 (100 × 2.1 mm, 2.6 µm) column with a gradient mobile phase system consisting of 2 mM ammonium acetate and 0.1% formic acid in acetonitrile at a flow rate of 0.25 mL/min for 4 min. The selectivity, lower limit of quantification, linearity, precision, accuracy, stability, recovery, and matrix effect of this developed method was validated according to the guidelines of the U.S. Food and Drug Administration and the Ministry of Food and Drug Safety of Korea. The established method achieved acceptance criteria in all validation parameters, ensuring reliability, reproducibility, and accuracy, and was successfully implemented in a pharmacokinetic study on the co-administration of DPZ and TAD orally in rats.

Ferric citrate in the management of hyperphosphataemia and iron deficiency anaemia: A meta-analysis in patients with chronic kidney disease.

AIMS: Phosphate-lowering effects of ferric citrate were reported in several clinical trials, but mostly in small-scale studies. The aim of this meta-analysis was to investigate the efficacy and safety of ferric citrate in controlling hyperphosphataemia and iron-deficiency anaemia in chronic kidney disease (CKD) patients. METHODS: PubMed, Embase and Cochrane Library were searched for clinical trials that enrolled CKD patients receiving ferric citrate for hyperphosphataemia. Two investigators performed systematic literature search to identify eligible studies, evaluated risk of bias and extracted relevant data. RESULTS: Sixteen studies were included in the meta-analysis. Phosphate-lowering effects of ferric citrate were greater compared to no active treatment (standardized mean difference [SMD] = -1.15; P < 0.001) and comparable to other phosphate binders (SMD = 0.03; P = 0.61). Calcium concentrations post ferric citrate treatment did not differ compared to no active treatment (SMD = 0.15; P = 0.21) but were significantly lower compared to other phosphate binders (SMD = -0.14; P = 0.01). These led to significant reductions in calcium-phosphorus product with ferric citrate versus no active control (SMD = -1.02; P < 0.001) but no difference versus active control (SMD = -0.01; P = 0.93). Intact parathyroid hormone showed no substantial between-group difference in both comparison against no active and active controls. Ferric citrate improved iron stores and anaemia parameters, but increased risk of diarrhoea, abdominal pain and discoloured faeces. CONCLUSION: Ferric citrate was effective in lowering phosphorus and phosphorus-calcium product versus no active treatment and had comparable effects versus other phosphate binders. Calcium levels were significantly lower with ferric citrate than with other phosphate-lowering treatment. Ferric citrate had additive effects on iron repletion and anaemia control and was associated with mostly gastrointestinal side effects.

Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-ß-DLX2 Signaling in the A549 Human Lung Cancer Cell Line.

Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-ß1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability.

Impact of a multidisciplinary quality improvement initiative to reduce inappropriate usage of stress ulcer prophylaxis in hospitalized patients.

AIMS: To promote effective methods to improve overutilization patterns of acid-suppressive therapy in hospitalized patients and to evaluate the impact of multidisciplinary team efforts to reduce inappropriate use of stress ulcer prophylaxis in low-risk patients. METHODS: A multidisciplinary quality improvement initiative incorporating education, medication use reviews and reconciliation, and pharmaceutical intervention was implemented in June 2018 for surgical patients hospitalized via emergency department. For the pre-post analysis and time series analysis, patients admitted during April and May were classified into the pre-intervention cohort and those admitted during July and August into the post-intervention cohort. RESULTS: Three hundred and seventeen patients were included in this study (153 and 164 in the pre- and post-intervention cohorts, respectively). The multidisciplinary program was effective in reducing overuse of stress ulcer prophylaxis and healthcare expenses associated with it. Biweekly education on risk factors warranting stress ulcer prophylaxis was provided for clinicians, and acid-suppressive therapy was removed from a preset list of admission orders. The incidence of inappropriate prophylaxis use declined substantially following intervention in overall patients (OR = 0.51, P = 0.01) and a significant decrease was primarily observed among non-ICU patients (OR = 0.50, P = 0.01). Interrupted time series analysis confirmed the significant decline in inappropriate use post intervention (coefficient = -0.63, P < 0.001). The total healthcare expenses associated with such overuse decreased by 58.5% from US$ 19.39 to US$ 8.04 per 100 patient-days. CONCLUSIONS: Our multidisciplinary team efforts were associated with improvement in stress ulcer prophylaxis overuse patterns, resulting in a substantial decrease in the incidence of inappropriate use, especially in general wards, and associated healthcare costs.

Stimulating DDX3 expression by serotonin 5-HT receptor 7 through phosphorylation of p53 via the AC-PKA-ERK signaling pathway.

DDX3 is a host viral factor that can inhibit the hepatitis B virus-induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5-HT upregulated DDX3 promoter activity via the 5-HT7 receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription-polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5-HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5-HT7 receptor by transfection si-5-HT7 receptors or si-control into HepG2 cells treated by 5-HT (or 5-HT plus agonist) confirmed the role of the 5-HT7 receptor in DDX3 expression. The IFN-ß-Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5-HT7 agonist (AS-19) increased IFN-ß expression and inhibited HBV replication. Luciferase assays showed the involvement of 5-HT7 receptors in DDX3 expression via cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS-19 mediated DDX3 promoter activated PKA extracellular signal-regulated kinase ERK signaling the p53 phosphorylation (-1080/-1070) resulted in upregulation of DDX3 promoter transactivation via the 5-HT7 receptors agonist. Overall, 5-HT7 was found to be a new potential target to inhibit hepatitis B infection by activating AC/PKA/ERK pathways by phosphorylating p53 via the 5-HT7 agonist response by mediating DDX3 expression.

Effect of pharmacy-led medication reconciliation in emergency departments: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Medication reconciliation is recommended to be performed at every transition of medical care to prevent medication errors or adverse drug events. This study investigated the impact of pharmacy-led medication reconciliation on medication discrepancies and potential adverse drug events in the ED to assess the benefits of pharmacy services. METHODS: The systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The PubMed, Ovid Embase and Cochrane library databases were searched up from inception to 1 July 2018. Studies comparing the effectiveness of the medication reconciliation service performed by pharmacy personnel to usual care (nurses or physicians) in the ED were included. Duplicated studies, non-clinical studies, studies with ineligible comparators or study designs were excluded. RESULTS AND DISCUSSION: Eleven studies were eligible for qualitative analysis, and 8 studies were included in meta-analysis. Pharmacy-led medication reconciliation substantially reduced medication discrepancies in the ED. The most common medication discrepancies included medication omission and incorrect/omitted dose or frequency. Unlike usual care, pharmacy-led medication reconciliation significantly reduced the proportion of patients with medication discrepancies by 68% (response rate 0.32; 95% confidence interval (CI): 0.19-0.53, P < .0001) and the number of medication discrepancy events by 88% (response rate 0.12; 95% CI 0.06-0.26, P < .00001). Intervention decreased the number of discrepancies per patient by 3.08 (mean difference -3.08; 95% CI: -4.76 to -1.39, P = .0003). Subgroup analysis revealed no differences between pharmacists and pharmacy technicians in medication reconciliation performance pertaining to medication discrepancies. The patients with several comorbidities or those administered numerous medications received marked benefits related to reduced medication discrepancies from pharmacy-led medication reconciliation. Moreover, a randomized controlled trial revealed decreased risk of potential adverse drug events by pharmacy-led medication reconciliation in patients receiving care in the ED. WHAT IS NEW AND CONCLUSION: Pharmacy-led medication reconciliation significantly decreased the number of medication discrepancies. However, only one study investigated potential adverse drug events in patients receiving care in the ED. Therefore, further studies investigating the direct clinical impact of decreased medication discrepancies are required.

N'-[(E)-Arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)-acetohydrazides: Synthesis and Evaluation of Caspase Activation Activity and Cytotoxicity.

In our search for novel small cytotoxic molecules potentially activating procaspase-3, we have designed and synthesized a series of novel N'-[(E)-arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)acetohydrazides (5, 6). Biological evaluation revealed that seven compounds, including 5h, 5j, 5k, 5l, 5n, 6a, and 6b, exhibited moderate to strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Among these compounds, two most cytotoxic compounds (5h and 5j) displayed from 3- up to 10-fold higher potency than PAC-1 and 5-FU in three cancer cell lines tested. Three compounds 5j, 5k, and 5n were also found to display better caspases activation activity in comparison to PAC-1. Especially, compound 5k activated the level of caspases activity by 200% higher than that of PAC-1. From this study, three compounds 5j, 5k, and 5n could be considered as potential leads for further design and development of caspase activators and anticancer agents.

Alleviation of hepatic fat accumulation by betaine involves reduction of homocysteine via up-regulation of betaine-homocysteine methyltransferase (BHMT).

We investigated the anti-lipogenic effect of betaine in rats fed methionine and choline-deficient diet (MCD). Intake of MCD for 3 wk resulted in a significant accumulation of hepatic lipids, which was prevented by betaine supplementation in drinking water (1%). Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein-1c (SREBP-1c), and liver kinase B1 (LKB1) was inhibited by MCD intake, and these changes were all inhibited by betaine feeding. Meanwhile, betaine supplementation reversed the reduction of methionine and S-adenosylmethionine (SAM), and the elevation of homocysteine levels in the liver, which could be attributable to the induction of betaine-homocysteine methyltransferase (BHMT) and methionine adenosyltransferase (MAT). Different cell lines were used to clarify the role of homocysteine on activation of the AMPK pathway. Homocysteine treatment decreased pAMPK, pACC, pSREBP-1c and pLKB1 in HepG2 cells. Metformin-induced activation of AMPK was also inhibited by homocysteine. Treatment with hydroxylamine, a cystathionine ß-synthase inhibitor, resulted in a reduction of pAMPK, pACC and pSREBP-1c, accompanied by an elevation of intracellular homocysteine. Betaine treatment prevented the homocysteine-induced reduction of pAMPK, pACC, pSREBP-1c and pLKB1 in H4IIE cells, but not in HepG2 cells. Also the elevation of cellular homocysteine and inhibition of protein expression of BHMT were prevented by betaine only in H4IIE cells which express BHMT. The results suggest that the beneficial effect of betaine against hepatic lipid accumulation may be attributed, at least in part, to the depletion of homocysteine via up-regulation of BHMT in hepatocytes.

Impact of institutional quality improvement initiatives on metabolic monitoring in mental disorder in patients treated with antipsychotics: A meta-analysis of intervention studies.

Background: Compliance with guidelines regarding monitoring of metabolic adverse effects induced by antipsychotics has been consistently low. We characterised and evaluated the quality of institutional quality improvement (QI) interventions designed to address disparities between guidelines and real-world practices. Furthermore, we assessed the impact of these interventions on the screening and management of metabolic risks for inpatients receiving treatment with antipsychotic medications. Methods: We conducted a meta-analysis of institutional QI intervention studies aimed at improving antipsychotic-associated metabolic risk monitoring in hospitalised mental disease patients. Relevant studies were identified through searches conducted in the Embase and PubMed databases, as well as by reviewing previous reviews and meta-analyses. Quantitative analyses were performed, calculating odds ratios (ORs) and 95% confidence intervals (CIs) to assess the impact of QI programmes on guideline adherence in clinical practice. Results: We identified 12 intervention studies (n = 10 128 and n = 2667 patients in the pre-and post-intervention groups, respectively) and included them in our meta-analysis. QI interventions demonstrated effectiveness in bridging the guideline-practice gap in monitoring antipsychotic-induced metabolic adverse effects, as supported by the ORs and 95% CIs for post-intervention monitoring of plasma glucose, lipids, and blood pressure (BP) vs the pre-intervention period being OR = 6.90 (95% CI = 1.51-31.48), OR = 5.39 (95% CI = 4.01-7.24), and OR = 4.81 (95% CI = 1.23-18.79), respectively. Only 33.3% (4/12) of studies reported screening rates for all four metabolic parameters (plasma glucose, lipids, weight/body mass index (BMI), and BP). The median rates for metabolic screening of plasma glucose, lipids, and BP increased from 51.0-80.0%, 28.7-66.7%, and 91.7-95.8%, respectively. Up to 66.7% (8/12) of intervention studies lacked follow-up measures to treat or manage identified risks in hospitalised psychiatric patients, such as patient referrals, prescription of medications, and switching of antipsychotics. The odds of monitoring weight/BMI and glucose were greatest when QI programmes involved the participation of multidisciplinary health care professionals and patients, yielding OR = 3.35 (95% CI = 2.45-4.59) and OR = 57.51 (95% CI = 24.11-137.21), respectively. Conclusions: Institutional QI interventions were effective in enhancing monitoring practices in alignment with established guidelines for metabolic risk screening among hospitalised patients with mental disorders maintained on antipsychotic medications. Future institutional QI programmes should incorporate multidisciplinary strategies involving patient engagement and extend their focus beyond screening to incorporate follow-up risk management strategies once risks have been identified. Registration: PROSPERO CRD42023452138.

Risk of Dementia and Alzheimer's Disease Associated With Antidiabetics: A Bayesian Network Meta-Analysis.

INTRODUCTION: Dementia risk is substantially elevated in patients with diabetes. However, evidence on dementia risk associated with various antidiabetic regimens is still limited. This study aims to comprehensively investigate the risk of dementia and Alzheimer's disease (AD) associated with various antidiabetic classes. METHODS: Cochrane Central Register of Controlled Trials, Embase, MEDLINE (PubMed), and Scopus were searched from inception to March 2024 (PROSPERO CRD 42022365927). Observational studies investigating dementia and AD incidences after antidiabetic initiation were identified. Bayesian network meta-analysis was performed to determine dementia and AD risks associated with antidiabetics. Preferred Reporting Items for Systematic Reviews-Network Meta-Analyses (PRISMA-NMA) guidelines were followed. Statistical analysis was performed and updated in November 2023 and March 2024, respectively. RESULTS: A total of 1,565,245 patients from 16 studies were included. Dementia and AD risks were significantly lower with metformin and sodium glucose co-transporter-2 inhibitors (SGLT2i). Metformin displayed the lowest risk of dementia across diverse antidiabetics, whereas α-glucosidase inhibitors demonstrated the highest risk. SGLT2i exhibited the lowest dementia risk across second-line antidiabetics. Dementia risk was significantly higher with dipeptidyl peptidase-4 inhibitor (DPP4i), metformin, sulfonylureas, and thiazolidinediones (TZD) compared to SGLT2i in the elderly (≥75 years). Dementia risk associated with metformin was substantially lower, regardless of diabetic complication status or baseline A1C. DISCUSSION: Metformin and SGLT2i demonstrated lower dementia risk than other antidiabetic classes. Patient-specific factors may affect this relationship and cautious interpretation is warranted as metformin is typically initiated at an earlier stage with fewer complications. Hence, further large-scaled clinical trials are required.

Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysis.

BACKGROUND: Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). METHODS: A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). RESULTS: Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 - 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) -0.25; 95% CI -0.69 - 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI -0.27-1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 - 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. CONCLUSION: The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.

Incident infection risks depending on oral antidiabetic exposure in insulin-treated type 2 diabetes patients.

Dipeptidyl peptidase-4 inhibitors (DPP4is) and sodium glucose cotransporter-2 inhibitors (SGLT2is) have been speculated to have a potential to increase infection risks in type 2 diabetes mellitus (T2DM) patients. We performed a cohort study using the Korean health insurance data to investigate infection risks with each drug class relative to metformin in insulin-treated T2DM patients. After propensity score matching, we included 1,498 and 749 patients in DPP4i + insulin vs metformin + insulin and 300 and 549 patients in SGLT2i + insulin vs metformin + insulin, respectively. In stratified analyses per patient factor, none of the odds ratios (ORs) were associated with a statistical significance across respiratory, genital, and urinary tract infections (UTIs), except that of the male stratum for respiratory infections (OR 0.77, p = 0.04). With regard to SGLT2is, a higher risk of genital infections was analyzed with their use than with metformin therapy (OR 1.76, p = 0.03). In stratified analyses, the OR for genital infections remained significant in the baseline cardiovascular disease stratum (OR 2.29, p = 0.01). No increased UTI risk was detected with SGLT2is compared against metformin. In this study on insulin-receiving T2DM patients, DPP4is were not associated with increased infection risks, whereas SGLT2is led to a higher risk for genital infections, but not for UTIs, relative to metformin.

Impact of metformin on statin-associated myopathy risks in dyslipidemia patients.

A growing number of patients with metabolic disorders are receiving statin and antidiabetic therapies as comedications. A signal of increased risk of myotoxicity due to potential interactions between antidiabetics and statins has been detected in previous studies. To investigate the effects of metformin on myopathy risks when added to preexisting statin therapy in dyslipidemia patients, we performed a retrospective cohort study using the Korean national health insurance data in statin-treated dyslipidemia patients with or without concomitant metformin use. We compared the risk of myopathy in statin + metformin users against statin-only users. Hazard ratios (HRs) and 95% confidence intervals (CIs) have been calculated following propensity score (PS) matching between study groups and subsequent stratification per patient factors. We included 4092 and 8161 patients in PS-matched statin + metformin and statin-only groups, respectively. The risk of myopathy decreased when metformin was used together with statins (adjusted HR 0.84; 95% CI 0.71-0.99). In subgroup analyses per individual statin agent and in stratified risk analyses, no specific statin agents or patient factors were associated with statistically significant myopathy risk. This study found that a comedication with metformin was associated with decreased myopathy risk in statin-treated dyslipidemia patients compared to statin-only users. Our findings suggest that metformin may provide protective effects on potential muscle toxicities induced by statin therapy.

A nationwide pharmacovigilance investigation on trends and seriousness of adverse events induced by anti-obesity medication.

Introduction: Despite rising concerns regarding the safety of anti-obesity medications, there is a lack of comprehensive pharmacovigilance investigations utilising real-world data. We aimed to characterise the prevalence and seriousness of adverse drug events (ADEs) related to anti-obesity medications and to identify predictors associated with increased risk of serious adverse events (SAE), thereby conveying evidence on drug safety. Methods: We conducted a cross-sectional analysis on ADE cases spontaneously reported to the Korea Adverse Event Reporting System Database (KIDS-KD). ADE reports pertaining to anti-obesity medications prescribed for overweight, obesity (International Classification of Disease, 10th revision (ICD-10) code E66) and abnormal weight gain (ICD-10 code E63.5) were included in the analysis. We performed a disproportionality to detect the association of the system organ class-based ADEs with their seriousness an individual's sex by estimating reporting odds ratios (RORs) and their 95% confidence intervals (CIs). We performed logistic regression to investigate factors that are substantially associated with increased SAE risks by estimating odds ratio (OR) and their 95% CIs. Results: The most common causative anti-obesity medication was phentermine, followed by liraglutide. ADEs associated with psychiatric disorders (ROR = 1.734; 95% CI = 1.111-2.707), liver and biliary system disorders (ROR = 22.948; 95% CI = 6.613-70.635), cardiovascular disorders (ROR = 5.707; 95% CI = 1.965-16.574), and respiratory disorders (ROR = 4.567; 95% CI = 1.774-11.762) were more likely to be serious events. Additionally, men are more likely to experience ADEs related gastrointestinal disorders (ROR = 1.411) and less likely to have heart and rhythm disorders (ROR = 0.507). The risk of SAE incidences was positively correlated with being male (OR = 2.196; 95% CI = 1.296-3.721), dual or triple combination of anti-obesity medications (OR = 3.258; 95% CI = 1.633-6.501 and OR = 8.226; 95% CI = 3.046-22.218, respectively), and concomitant administration of fluoxetine (OR = 5.236; 95% CI = 2.218-12.365). Conclusions: Seriousness of anti-obesity medication-related ADEs differs among system-organ class, while sex-related differences in ADE profiles are also present. The predictors substantially increasing risk of SAE incidences include being male, having a higher number of concomitant medications (including multiple combination of anti-obesity medications), and concurrent use of fluoxetine. Nonetheless, further pharmacovigilance investigation and monitoring are needed to enhance awareness on ADEs induced by anti-obesity medications.

Clinical outcomes of renin angiotensin system inhibitor-based dual antihypertensive regimens in chronic kidney disease: a network meta-analysis.

This study comprehensively investigated clinical outcomes associated with renin angiotensin system inhibitor-based dual antihypertensive regimens in non-dialysis chronic kidney disease (CKD) patients. Keyword searches of databases were performed per PRISMA-NMA guidelines. Frequentist network meta-analysis were conducted with 16 head-to-head randomized controlled trials. The effect sizes of dichotomous and continuous variables were estimated with odds ratio (OR) and standard mean differences (SMD), respectively. The protocol is registered in PROSPERO (CRD42022365927). Dual antihypertensive regimens with combination of angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) demonstrated substantially reduced odd of major cardiovascular disease (CVD) events over other regimens including angiotensin converting enzyme inhibitor (ACEI) monotherapy (OR 3.19) and ARB monotherapy (OR 2.64). Most significant reductions in systolic (SBP) and diastolic blood pressure (DBP) were observed with ARB-based CCB dual regimen over ACEI monotherapy (SMD 17.60 SBP and 9.40 for DBP), ACEI-based CCB regimen (SMD 12.90 for SBP and 9.90 for DBP), and ARB monotherapy (SMD 13.20 for SBP and 5.00 for DBP). However, insignificant differences were noticed for the odds of hyperkalemia, end stage renal disease progression, and all-cause mortality. ARB-based CCB regimen has the greatest benefits on BP reduction as well as major CVD risks in non-dialysis CKD patients.

A Real-World Data Driven Pharmacovigilance Investigation on Drug-Induced Arrhythmia Using KAERS DB, a Korean Nationwide Adverse Drug Reporting System.

This study aims to investigate the prevalence and seriousness of drug-induced arrhythmia and to identify predictors associated with the seriousness of arrhythmia. Drug-induced arrhythmia cases reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. A disproportionality test was performed to detect the association of the etiologic medication classes and types, along with patient demographic information, with the seriousness of drug-induced arrhythmia. Logistic regression was performed to investigate the predictors that increase the risk of serious arrhythmia. The most common etiologic agent for drug-induced arrhythmia was sevoflurane, whereas serious arrhythmia was most prevalent with narcotics. Antibiotics (reporting odds ratio (ROR) 4.125; 95% CI 1.438-11.835), chemotherapy (ROR 6.994; 95% CI 2.239-21.542), and iodinated contrast media (ROR 8.273; 95% CI 3.062-22.352) had a strong association with the seriousness of drug-induced arrhythmia. Among numerous etiologic agents, ioversol (ROR 16.490; 95% CI 3.589-75.772) and lidocaine (ROR 12.347; 95% CI 2.996-50.884) were more likely to be reported with serious arrhythmia. Aging and comorbidity, primarily cancer, are the most contributing predictors associated with serious arrhythmia. Further studies on the clinical significance of patient-specific predictors for the increased risk of serious drug-induced arrhythmia are warranted to promote drug safety.

A Real-World Data Derived Pharmacovigilance Assessment on Drug-Induced Nephropathy: Implication on Gaps in Patient Care.

This retrospective cross-sectional study aims to investigate the prevalence and seriousness of drug-induced nephrotoxicity and to identify clinical predictors intensifying the seriousness of nephrotoxicity. Adverse drug events (ADEs) reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. The association between the seriousness and the etiologic drug was estimated in reporting odds ratio (ROR) based on disproportionality analysis. Logistic regression was utilized to recognize predictors associated with serious nephrotoxicity. The majority of ADEs were reported in ages 30 to 59, and immunosuppressants were the most etiologic medications. ADEs involving antibiotics, including vancomycin (ROR 0.268; 95% CI 0.129-0.557), were less likely to be serious. More than 93% of cyclosporine-related ADEs were serious nephrotoxicity, whereas tacrolimus was less likely to report serious nephrotoxicity (ROR 0.356; 95% CI 0.187-0.680). The risk of serious nephrotoxicity was decreased with aging (ROR 0.955; 95% CI 0.940-0.972) while increased in women (OR 2.700; 95% CI 1.450-5.008). Polypharmacy was associated with increased risk of interstitial nephritis (OR 1.019; 95% CI 1.001-1.038). However, further studies investigating the impact of clinical practice on ADE incidences as well as clinical prognosis related to nephrotoxicity are obligated.

The DEAD-box RNA helicase DDX3 interacts with DDX5, co-localizes with it in the cytoplasm during the G2/M phase of the cycle, and affects its shuttling during mRNP export.

DDX3 is involved in RNA transport, translational control, proliferation of RNA viruses, and cancer progression. From yeast two-hybrid screening using the C-terminal region of DDX3 as a bait, the DEAD-box RNA helicase DDX5 was cloned. In immunofluorescence analysis, DDX3 and DDX5 were mainly co-localized in the cytoplasm. Interestingly, cytoplasmic levels of DDX5 increased in the G(2) /M phase and consequently protein-protein interaction also increased in the cytoplasmic fraction. DDX3 was highly phosphorylated at its serine, threonine, and tyrosine residues in the steady state, but not phosphorylated at the serine residue(s) in the G(2) /M phase. DDX5 was less phosphorylated in the G(1) /S phase; however, it was highly phosphorylated at serine, threonine, and tyrosine residues in the G(2) /M phase. PP2A treatment of the cytoplasmic lysate from G(2) /M phase cells positively affected the interaction between DDX3 and DDX5, whereas, PTP1B treatment did not. In an analysis involving recombinant His-DDX3 and His-DDX5, PP2A pretreatment of His-DDX5 increased the interaction with endogenous DDX3, and vice versa. Furthermore, the results of GST pull-down experiments support the conclusion that dephosphorylation of serine and/or threonine residues in both proteins enhanced protein-protein interactions. UV cross-linking experiments showed that DDX3 and DDX5 are involved in mRNP export. Additionally, DDX3 knockdown blocked the shuttling of DDX5 to the nucleus. These data demonstrate a novel interaction between DDX3 and DDX5 through the phosphorylation of both proteins, especially in the G(2) /M phase, and suggest a novel combined mechanism of action, involving RNP remodeling and splicing, for DEAD-box RNA helicases involved in mRNP export.