Advancing drug safety and mitigating health concerns: High-resolution mass spectrometry in the levothyroxine case study.

Levothyroxine is a drug with a narrow therapeutic index. Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems. However, the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed. In this study, we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes. Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry (UHPLC-DIA-HRMS) was employed. UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products, but also the presence of non-expected components in the formulations. Among these, we identified compounds resulting from reactions between mannitol and other excipients, such as citric acid, stearate, and palmitate, or from reactions between an excipient and an active pharmaceutical ingredient, such as levothyroxine-lactose adduct. In addition to these compounds, undeclared phospholipids were also found in three formulations. This non-targeted approach is not common in pharmaceutical quality control analysis. Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.

A disproportionality analysis for assessing the safety of FLT3 inhibitors using the FDA Adverse Event Reporting System (FAERS).

Objectives: This pharmacovigilance analysis was conducted to assess the safety signals of FMS-related tyrosine kinase 3 (FLT3) inhibitors in a real-world setting using the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Design: We analyzed adverse event (AE) reports related to FLT3 inhibitors submitted to the FAERS database from the first quarter of 2015 to the fourth quarter of 2022. Disproportionality analysis was used to identify AEs of FLT3 inhibitors in the FAERS database. Results: A total of 55,393 AE reports were identified, of which 5938, 44,013, and 5442 were attributed to midostaurin, sorafenib, and gilteritinib, respectively, as primary suspects. Compared to the full database, significant safety signals at the system organ class level were observed for midostaurin (blood and lymphatic system disorders and hepatobiliary disorders), sorafenib (skin and subcutaneous tissue disorders and hepatobiliary disorders), and gilteritinib (investigations, blood and lymphatic system disorders, infections and infestations, and hepatobiliary disorders). All the drugs studied were associated with hepatobiliary disorders. The most prominent AEs associated with midostaurin, sorafenib, and gilteritinib were cytopenia, palmar-plantar erythrodysesthesia syndrome, and increased blast cell count, respectively. Compared with chemotherapy, midostaurin and gilteritinib showed a higher risk of electrocardiogram QT prolongation, gastrointestinal hemorrhage, cerebral hemorrhage, and increased white blood cell count. Gilteritinib had the highest overall death percentage (30.28%), whereas sorafenib had the lowest (23.06%). Conclusion: Mining AE signals using the FAERS database provides a method for analyzing the safety of FLT3 inhibitors in post-marketing. We found several significant AE signals that corresponded to previous studies; however, some AE signals were not mentioned in the drug instructions. Our study could provide a direction for follow-up real-world studies to verify the results further.

Introduction: The United States Food and Drug Administration Adverse Event Reporting System (FAERS) is an essential tool for the United States Food and Drug Administration (FDA) to detect adverse events (AE). This study explored the safety signals of FMS-related tyrosine kinase 3 (FLT3) inhibitors (midostaurin, sorafenib, and gilteritinib) using the FAERS database. Research design and methods: We used reporting odds ratios, proportional reporting ratios, and Bayesian confidence propagation neural network to analyze the safety signals of FLT3 inhibitors by comparing them with the full database and chemotherapy agents from 2015 to 2022. Results: A total of 5,938, 44,013, and 5,442 reports were attributed to midostaurin, sorafenib, and gilteritinib, respectively. Based on the analysis results, we observed the following:• Regarding the analysis of system organ class level compared with the full database, "hepatobiliary disorders" appeared as an important signal in all three drugs. In addition, "blood and lymphatic system disorders" of midostaurin, "skin and subcutaneous tissue disorders" of sorafenib, and "investigations," "blood and lymphatic system disorders," and "infections and infestations" of gilteritinib were significant.• Cytopenia was the most prominent AE associated with midostaurin in comparisons of midostaurin versus the full database, and electrocardiogram QT prolonged was the strongest signal in comparisons of midostaurin versus chemotherapy.• In both comparisons of FLT3 inhibitors versus the full database and chemotherapy, the strongest safety signals of sorafenib and gilteritinib were palmar-plantar erythrodysesthesia syndrome and increased blast cell count, respectively.• Gilteritinib exhibited the highest overall mortality rate, whereas sorafenib had the lowest. Conclusion: We identified several significant AE signals that corresponded to previous studies. However, some AE signals were not mentioned in the drug instructions. The AE signals should be evaluated further based on real-world data in the future.

A study on the adverse effects of FLT3 inhibitors.

High-risk pediatric medications: A listing proposal by interdisciplinary consensus technique. / Medicación pediátrica de alto riesgo: propuesta de listado a través de la técnica de consenso interdisciplinar.

INTRODUCTION: Pediatric patients are more likely to experience medication-related errors and serious associated harms. The identification of high-risk medications (HRM) and their study in special populations, such as children with excess body weight, is a part of safety improvement strategies. OBJECTIVE: To generate, through a consensus technique structured by an interdisciplinary group of pediatricians and hospital pharmacists, an operational and updated list of HRM for hospital use in children over 2 years of age. The document was part of a collaboration project between the Spanish Society of Hospital Pharmacists and the Spanish Society of Pediatric Hospital Medicine. METHODS: The study was carried out in two sequential phases: a) preparation of a preliminary list of HRM through bibliographic review and b) subsequent application of the double-round Delphi method to agree on a definitive list of HRM. The results obtained were validated by calculating the probability of chance agreement and the modified Kappa statistic for each drug. RESULTS: The original list obtained by bibliographic review included 26 pharmacological classes and 96 drugs. Of the total of 37 experts, 32 (86.4%) completed both rounds of the Delphi. The final consensus list of HRM incorporated 24 pharmacological classes and 100 drugs. The modified Kappa statistic reflected a high percent agreement (94.9%) in the consensus reached by the participants. CONCLUSION: This list can establish a tool for future studies and interventions to improve the safety of medications in general pediatric population, as well as in high-risk subgroups, such as pediatric patients with excess body weight.

Post-marketing safety profile of solriamfetol: A real-world disproportionality analysis using FDA adverse event reporting system (FAERS) database.

Solriamfetol is a selective dopamine and noradrenalin reuptake inhibitor applied in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). However, the post-marketing safety profile of solriamfetol in large number of people was unrevealed. The purpose of our study is to unravel solriamfetol's adverse events (AEs) in real-world to refine medication safety using Food and Drug Administration Adverse Event Reporting System (FAERS) database. We derived the data associated with solriamfetol from FAERS between 2019 and 2023, and removed the duplicated entries. We evaluated the disproportionality of solriamfetol's AEs by reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS). Among 8,846,085 AE reports, 1659 recorded solriamfetol as the 'primary suspected (PS)'. 74 significant disproportionality preferred terms (PTs) were retained across 27 organ systems. Moreover, 16 unexpected AEs not mentioned in the FDA label of solriamfetol were identified. Our findings provided the post-marketing safety profile of solriamfetol, highlighting potential solriamfetol's AEs. Further researches are significant to define the causality between solriamfetol and newly identified AEs.

Adverse event profiles of CDK4/6 inhibitors: data mining and disproportionality analysis of the FDA adverse event reporting system.

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are targeted therapies designed to selectively block CDK4/6, crucial regulators of the cell cycle. These inhibitors play a pivotal role in restoring cell cycle control, particularly in breast cancer cases marked by abnormal CDK regulation, ultimately inhibiting uncontrolled cell division and tumor growth. Objectives: This analysis aimed to comprehensively examine adverse effects in CDK4/6 inhibitors using the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Design: Disproportionality analysis was conducted to analyze the adverse event (AE) reports related to CDK4/6 inhibitor submitted to the FAERS database. Methods: We collected AE reports regarding palbociclib, ribociclib, abemaciclib, trilaciclib, and dalpiciclib submitted to the FAERS from 2015Q1 to 2023Q1. We used the system organ class and the Standardized MedDRA Query to perform a comprehensive search for AEs at the preferred term (PT) level, using case reports as our data source. After removing duplicate reports, we performed disproportionality analysis and sensitivity analysis to identify safety signals. Results: A total of 85,635 reports encompassing 280,211 AEs were extracted for analysis. Among 3681 scrutinized PTs, approximately 484 were detected as statistically significant signals associated with CDK4/6 inhibitors. It was noteworthy that palbociclib and ribociclib had comparable safety profiles, whereas abemaciclib exhibited distinctive safety patterns. Notably, our analysis found novel safety signals linked to CDK4/6 inhibitors, including nail-related disorders such as onychoclasis, nail disorder, and nail discoloration, and psychiatric concerns, including eating disorders and emotional disorder. Conclusion: Overall, the present study identified several new safety signals of CDK4/6 inhibitors, as well as differences among various drugs within the CDK4/6 category, through the use of the FDA FAERS, which deserve more careful monitoring in the clinic.

Introduction: An adverse event (AE) refers to any undesirable or harmful occurrence that happens to an individual during or after the use of a medical product or intervention. These events are typically reported to regulatory authorities, such as the Food and Drug Administration (FDA), to ensure the safety and effectiveness of medical products. The United States Food and Drug Administration Adverse Event Reporting System (FAERS) database plays a pivotal role in identifying these adverse events. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are a class of drugs used to treat certain types of cancer by inhibiting the growth and division of cancer cells. This study investigated the safety signals related to CDK4/6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, by using the FAERS database. Methods: We collected AE reports associated with CDK4/6 inhibitors that were submitted to the FAERS database between the first quarter of 2015 and the first quarter of 2023. Reporting odds ratio (ROR) method was used identify signals of AEs. Results: 85,635 AE reports were identified, approximately 484 AE terms were identified as positive signals. Palbociclib and ribociclib had similar safety profiles, while abemaciclib showed a unique pattern. Our analysis also revealed previously unreported AEs, including nail-related disorders such as onychoclasis, nail disorder and nail discolouration. Psychiatric concerns such as eating disorders and emotional disorder were also identified. Conclusion: We discovered important safety concerns related to CDK4/6 inhibitors. Some of these concerns were consistent with previous studies, while nail-related disorders, eating disorder and emotional disorder were new and not mentioned in the drug labels or existing literature. Our findings may help physicians and pharmacists to weigh the risks and benefits of using CDK4/6 inhibitors in clinical practice.

A study on the adverse effects of CDK4/6 inhibitors.

Re-Exposure to Culprit Medication Following Adverse Drug Event Diagnosis in Canadian Emergency Department Patients: A Cohort Study.

PURPOSE: The magnitude of repeat exposures to culprit medications after hospital discharge is not well studied. We combined prospective cohort data with administrative health data to understand the frequency of repeat exposures to culprit medications after discharge and the risk factors for their occurrence. METHODS: This was a retrospective analysis of three prospective cohorts of patients who presented to the hospital with an adverse drug event in British Columbia, from 2008 to 2015 (n = 849). We linked prospectively identified adverse drug events to administrative data to examine patterns of redispensing of culprit medications. We used Cox regression to assess risk factors for re-exposure, and conducted subgroup analyses for essential vs. nonessential medications. RESULTS: Among 849 diagnosed adverse drug events, 45.2% had subsequent culprit medication redispensing within a year of hospital discharge. The factors associated with re-exposures included atrial fibrillation, adverse drug event type (e.g. adverse reaction), culprit medication type, and longer historical duration of medication use. CONCLUSIONS: Re-exposures to culprit medications occurred in almost half of the adverse drug events diagnosed in emergency departments. Many of these were appropriate re-exposures to essential medications for indications in which the risk of uncontrolled disease likely outweighed the risk of a repeat adverse event. More research is needed to understand re-exposures to nonessential medications or medications with safer alternatives.

Fetal exposure to isotretinoin in Saudi Arabia: a multicenter real-world data analysis from 2015 to 2020.

Background: Despite its high efficacy in treating severe acne, isotretinoin is associated with serious side effects, including teratogenicity. However, the extent of isotretinoin exposure during pregnancy in Saudi Arabia remains unknown. Objectives: This study aims to quantify the extent of fetal exposure to isotretinoin in Saudi Arabia and to evaluate adherence to risk minimization measures approved by the Saudi Food and Drug Authority. Design: Retrospective cohort study. Methods: This multicenter retrospective study included a cohort of 6233 women of childbearing ages (WCBAs) who had received isotretinoin therapy between 2015 and 2020. Exposure to isotretinoin use was ascertained from patients' electronic health records and was defined as any positive pregnancy test (urine or serum) or any diagnosis or procedure related to pregnancy occurring during the risk period. We defined the risk period starting from isotretinoin initiation until up to 30 days after the last prescription. We quantified the overall incidence proportion of fetal exposure to isotretinoin by dividing the number of pregnancy cases during the risk period by the total study sample of WCBAs. Results: The cohort predominantly included young females (20-29 years), with a mean age of 24 years. Only 5% of the WCBAs used contraceptives, and 10% have a record of pregnancy testing. During the risk period, 34 pregnancies were identified, yielding a cumulative pregnancy incidence of 5.6 per 1000 WCBAs. Pregnancy outcomes for exposed women were about 5% of births had defects, while abortions accounted for 14.3% of pregnancies. Conclusion: Our investigation shows an alarming incidence of fetal exposure to isotretinoin in Saudi Arabia, substantially surpassing global estimates. These results underscore a critical need for enhanced interventions and robust risk minimization strategies tailored to the distinct challenges faced by the Saudi Arabian population.

Evaluating isotretinoin use during pregnancy in Saudi Arabia Why was the study done? Isotretinoin is highly effective for treating severe acne but is known to cause serious birth defects if used during pregnancy. The extent to which pregnant women in Saudi Arabia are exposed to isotretinoin was not known. Understanding this exposure is crucial to improve patient safety and adherence to preventive measures. What did the researchers do? The researchers conducted a retrospective study involving 6,233 women of childbearing age who received isotretinoin between 2015 and 2020. They used electronic health records from multiple healthcare institutions to identify cases of isotretinoin exposure during pregnancy. The study assessed the frequency of fetal exposure and evaluated adherence to risk minimization measures approved by the Saudi Food and Drug Authority (SFDA). What did the researchers find? The study found a significant incidence of fetal exposure to isotretinoin, with 5.6 cases per 1,000 women of childbearing age, which is much higher than global estimates. During the study period, 34 pregnancies were identified among isotretinoin users, with a notable percentage resulting in birth defects (5%) and abortions (14.3%). The adherence to contraceptive use (5%) and pregnancy testing (10%) among isotretinoin users was low, indicating a gap in following SFDA guidelines. What do the findings mean? These findings highlight a critical need for improved regulatory strategies and interventions to prevent fetal exposure to isotretinoin in Saudi Arabia. Enhanced measures might include better education on contraceptive use, stricter enforcement of pregnancy testing, and the integration of digital healthcare solutions to ensure adherence to safety protocols. This study sets a foundation for future efforts to improve the safe use of isotretinoin and protect unborn children from its harmful effects.

Association of anxiolytic drugs with Torsade de Pointes: a pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.

Background: This study aimed to determine the association of Torsade de Pointes (TdP) with anxiolytic drugs and present a detailed overview of anxiolytic-induced cases of TdP reported to the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: All cases of anxiolytic-induced TdP (n = 260) between 1990 and 2020 were retrieved from the FAERS database using the Preferred Term 'Torsade de Pointes, code: 10044066' from the Medical Dictionary for Regulatory Activities (MedDRA version 22). Four data-mining algorithms were used for disproportionality analysis: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC). Anxiolytics with ≥3 TdP cases were included. Results: Of a total of eight drugs, this study identified seven signals of TdP, of which six signals were new, namely for alprazolam, bromazepam, lorazepam, meprobamate, midazolam, and oxazepam. Based on disproportionality analysis, among new signals, the highest risk of TdP was observed with bromazepam and midazolam. Alprazolam showed the lowest risk for TdP, while diazepam did not reach significant disproportionality. Conclusions: This study identified six new signals of TdP among anxiolytic drugs, so warranting stringent clinical studies to ascertain the actual risk of TdP and ensure patient safety. Clinical Trial Registration: This study is registered at ClinicalTrials.gov (NCT.gov ID: NCT04293432).

A discovery and verification approach to pharmacovigilance using electronic healthcare data.

Introduction: Pharmacovigilance is vital for drug safety. The process typically involves two key steps: initial signal generation from spontaneous reporting systems (SRSs) and subsequent expert review to assess the signals' (potential) causality and decide on the appropriate action. Methods: We propose a novel discovery and verification approach to pharmacovigilance based on electronic healthcare data. We enhance the signal detection phase by introducing an ensemble of methods which generated signals are combined using Borda count ranking; a method designed to emphasize consensus. Ensemble methods tend to perform better when data is noisy and leverage the strengths of individual classifiers, while trying to mitigate some of their limitations. Additionally, we offer the committee of medical experts with the option to perform an in-depth investigation of selected signals through tailored pharmacoepidemiological studies to evaluate their plausibility or spuriousness. To illustrate our approach, we utilize data from the German Pharmacoepidemiological Research Database, focusing on drug reactions to the direct oral anticoagulant rivaroxaban. Results: In this example, the ensemble method is built upon the Bayesian confidence propagation neural network, longitudinal Gamma Poisson shrinker, penalized regression and random forests. We also conduct a pharmacoepidemiological verification study in the form of a nested active comparator case-control study, involving patients diagnosed with atrial fibrillation who initiated anticoagulant treatment between 2011 and 2017. Discussion: The case study reveals our ability to detect known adverse drug reactions and discover new signals. Importantly, the ensemble method is computationally efficient. Hasty false conclusions can be avoided by a verification study, which is, however, time-consuming to carry out. We provide an online tool for easy application: https://borda.bips.eu.

Suspected adverse drug reactions of rivaroxaban reported in the United States food and drug administration adverse event reporting system database: a pharmacovigilance study.

Purpose: This study aimed to characterize the safety profiles of rivaroxaban-associated suspected adverse events by mining the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A disproportionality analysis of spontaneously reported suspected adverse drug reactions (ADRs) was conducted. The reports in FAERS from 2014 to 2024 were compiled. Frequentist and Bayesian statistics were both applied to calculate drug-AE combinations in system organ classes and preferred-term levels. Reporting odds ratio (ROR), proportional reporting ratio (PRR), the Medicines and Healthcare products Regulatory Agency (MHRA), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods were analyzed and used to compare the suspected AEs. Results: Of 77,384 ADR reports, 66,705 (86.20%) were serious rivaroxaban AE reports. The most common age group was above 65 years. The suspected adverse effects of rivaroxaban emerging for system organ classes (SOCs) primarily included "Gastrointestinal disorders"; "Injury, poisoning, and procedural complications", "Nervous system disorders" and "Vascular disorders". Ranked by EBGM, the top signal strength of suspected AE signals of rivaroxaban under ROR algorithm at the preferred-term (PT) level were "Haemorrhagic arteriovenous malformation" (N = 571, ROR = 756.520, PRR = 754.029, Information Component (IC) = 7.197, Empirical Bayesian Geometric Mean (EBGM) = 146.725), "Gastrointestinal vascular malformation haemorrhagic" (N = 197, ROR = 211.138, PRR = 210.950, IC = 6.614, EBGM = 97.923), and "Diverticulum intestinal haemorrhagic" (N = 722, ROR = 169.898, PRR = 169.210, IC = 6.458, EBGM = 97.920). Moreover, uncommon but significantly suspected AE signals, such as "Coagulation factor X level increased", "Basal ganglia haematoma", and "Proctitis haemorrhagic" were observed. Notably, "Gastrointestinal haemorrhage" (N = 13,436, ROR = 80.477, PRR = 74.460, IC = 5.729, EBGM = 53.042), "Upper gastrointestinal haemorrhage"(N = 2,872, ROR = 73.978, PRR = 72.797, IC = 5.706, EBGM = 52.198) and "Internal haemorrhage" (N = 2,368, ROR = 91.979, PRR = 80.899, IC = 5.813, EBGM = 56.212) exhibited relatively high occurrence rates and signal strengths. From 2014 to 2024, the IC values of rivaroxaban-associated suspected AEs for "Surgical and medical procedures" and "Cardiac disorders" showed an annual increasing trend in the time-span analysis. Based on the various visulization plots, a key discovery is that "Gastrointestinal hemorrhage" emerged as the most significant suspected AE across five algorithms. The exciting finding was that the MGPS algorithm revealed a higher risk of suspected AEs under the "Investigations" category. However, the results of the analyses of the other algorithms at the SOC level were not akin to this. Moreover, the results of signal mining for the three main types of indication populations with adverse drug reactions (ADRs), including Atrial fibrillation, Cerebrovascular accident prophylaxis, and Deep vein thrombosis were shown that "Gastrointestinal haemorrhage", "Epistaxis", "Haematuria", "Rectal haemorrhage", and "Upper gastrointestinal haemorrhage" were detected as the most common and significant signals of suspected adverse events. Conclusion: Rivaroxaban has risks of various suspected adverse reactions while providing therapeutic effects and being used widely. Our pharmacovigilance study may provide valuable hints that practitioners should closely monitor occurrences of "Gastrointestinal disorders", "Injury, poisoning, and procedural complications" and "Nervous system disorders", and other events in clinical applications. Consequently, it remains to persist in monitoring rivaroxaban, assessing the associated risks in the future.

The Role of Quality Assurance in Clinical Trials: Safeguarding Data Integrity and Compliance.

Clinical trials, which investigate the effects of drugs in humans, aim to determine safety and efficacy while identifying adverse reactions. Data consistency and subject safety are crucial factors that determine the quality of clinical trials, necessitating overall quality management. There is a growing emphasis on implementing quality systems during the planning stages of clinical trials. Regulatory frameworks have evolved to ensure patient protection and data reliability, underscoring the need for systematic quality management in health research. A clinical trial quality management plan (CTQMP) is essential to describe the tools and methods used to ensure study quality. Globalization has led to an increase in conducting clinical trials in developing nations, presenting challenges due to procedural and ethical disparities. To manage these complexities, outsourcing trial management has become common. Adherence to good clinical practice (GCP) principles, as defined by the International Conference on Harmonization (ICH), is critical for safeguarding participant rights and ensuring credible data. Quality by design (QbD) and quality risk management are now central to clinical trial management, as advocated by the FDA. Technological advancements and robust protocols further enhance trial processes. Effective QA activities, including monitoring and data management, are vital for maintaining compliance, participant safety, and data integrity, highlighting the indispensable role of QA in clinical trial success.

Multimodal Analgesia Approach in Acute Low Back Pain Management: A Phase III Study of a Novel Analgesic Combination of Etoricoxib/Tramadol.

INTRODUCTION: Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. METHODS: We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90 mg/tramadol 50 mg (one packet of granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. RESULTS: One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% - 0.648 (- 0.010 to 1.306)] and 5 days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061-0.421)]. An improvement in LBP's disability to perform activities of daily routine (Oswestry and Roland-Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). CONCLUSIONS: The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04968158.

Toxicity profiles associated with EGFR-TKIs combined with angiogenesis inhibitors in non-small cell lung cancer: an epidemiological surveillance analysis of the FDA adverse event reporting system.

BACKGROUND: Ongoing studies are evaluating the efficacy and toxicity profiles of combining epidermal growth factor receptor inhibitors (EGFR-TKIs) with antiangiogenic agents in non-small cell lung cancer (NSCLC). However, the complete toxicity profiles remain elusive. RESEARCH DESIGN AND METHODS: This study conducted an extensive pharmacovigilance analysis utilizing the FDA Adverse Event Reporting System database. The analysis focused on identifying and characterizing adverse events (AEs) associated with the concurrent use of EGFR-TKIs and antiangiogenic inhibitors in patients with NSCLC. RESULTS: The study identified significant occurrences of AEs linked to the combination therapy, particularly impacting general disorders, skin and subcutaneous tissue conditions, and vascular disorders. Frequently reported AEs included rash, diarrhea, fatigue, nausea, decreased appetite, and anemia. Notably, the combination of EGFR-TKIs with antiangiogenic inhibitors resulted in an increased incidence of AEs across multiple organ systems compared to EGFR-TKIs alone, with some adverse effects, such as anemia, arrhythmia, and ulcerative keratitis, persisting beyond one year in a subset of patients. CONCLUSIONS: The combination of EGFR-TKIs and antiangiogenic inhibitors in NSCLC treatment presents a distinct and substantial AE profile, often with delayed onset. This finding underscores the necessity for rigorous and ongoing monitoring protocols to mitigate potential long-term adverse effects.

Kaempferia galanga L. alleviates the expression of COX-2 and NF-kappaB-p65 in the oral mucosa ulcer of Wistar rats and exhibits no irritation toward the vascular membrane of chicken eggs and the skin of albino rabbits.

The global incidence of recurrent aphthous stomatitis in 2018 reached 5-66 % of the population, while in Indonesia 8 %. Moreover, the prevalence of oral mucosal fibrosis and recurrent aphthous stomatitis among male doctors and nurses in China was 21.24 % and 24.27 %, respectively. Our previous study has shown that the ethanol extract of Kaempferia galanga L. rhizome (EKGR) revealed an accelerated wound-healing effect in the oral mucosa ulcer of Wistar rats. This study aims to explore the effects of EKGR on the expression of NF-kappaB-p65 and COX-2 in the tongue tissue of male Wistar rats by Western blot analysis and immunohistochemistry technique, its safety towards the vascular membrane of the egg chorioallantoic membrane, and its single-dose application on the skin of male rabbits. The rats were randomly assigned into 7 groups: the normal control; the negative control; the positive control (treated with triamcinolone acetonide); and 4 treatment groups of EKGR (0.5 %; 1 %; 2 %; 4 %). Western blot and immunohistochemistry methods were used to measure the expression of NF-kappaB-p65 and COX-2. The hen's egg test-chorioallantoic membrane assay was employed to predict the safety of EKGR towards the vascular membrane. Moreover, the effect of 200 mg/kg BW EKGR application on the dorsal skin of male albino rabbits was also evaluated. EKGR inhibits the expression of NF-kappaB-p65 and COX-2 as proven by WB and IHC results. In the HET-CAM assay, all concentrations of EKGR do not induce irritation responses, which elicits the safety of EKGR. The administration of EKGR causes mild irritation to the dorsal skin of male rabbits but does not induce erythema and edema, no significant changes in BW, no toxic effects on organ macroscopic examination or histopathology, and does not induce abnormalities in the hematological profile of male albino rabbits. EKGR has confirmed its anti-inflammatory activity by suppressing the expression of COX-2 and NF-kappaB-p65 in the oral mucosa ulcer of Wistar rats. EKGR is safe as it does not exhibit irritating potential and harmful effects.

Leveraging Generative AI for Drug Safety and Pharmacovigilance.

Predictions are made by artificial intelligence, especially through machine learning, which uses algorithms and past knowledge. Notably, there has been an increase in interest in using artificial intelligence, particularly generative AI, in the pharmacovigilance of pharmaceuticals under development, as well as those already in the market. This review was conducted to understand how generative AI can play an important role in pharmacovigilance and improving drug safety monitoring. Data from previously published articles and news items were reviewed in order to obtain information. We used PubMed and Google Scholar as our search engines, and keywords (pharmacovigilance, artificial intelligence, machine learning, drug safety, and patient safety) were used. In toto, we reviewed 109 articles published till 31 January 2024, and the obtained information was interpreted, compiled, evaluated, and conclusions were reached. Generative AI has transformative potential in pharmacovigilance, showcasing benefits, such as enhanced adverse event detection, data-driven risk prediction, and optimized drug development. By making it easier to process and analyze big datasets, generative artificial intelligence has applications across a variety of disease states. Machine learning and automation in this field can streamline pharmacovigilance procedures and provide a more efficient way to assess safety-related data. Nevertheless, more investigation is required to determine how this optimization affects the caliber of safety analyses. In the near future, the increased utilization of artificial intelligence is anticipated, especially in predicting side effects and Adverse Drug Reactions (ADRs).

Factors influencing safe use of drugs among community residents: a cross-sectional study.

BACKGROUND: Researchers have paid little attention to the safety of drug use among community residents (CRs). Irrational use of drugs can lead to health risks. We investigated the situation of knowledge-attitude-practices (KAP) of CRs in Shenzhen (China) for safe use of drugs, and analyzed the main factors influencing drug use. METHODS: A multi-stage, random sampling method was used. We used a validated questionnaire to conduct an online questionnaire survey on the demographic characteristics and KAP of safe use of drugs of CRs in 10 administrative districts of Shenzhen City. The KAP score of safe use of drugs of CRs was analyzed. Influencing factors were identified using a single-factor chi-squared test and binary logistic regression analysis. RESULTS: A total of 7269 valid questionnaires were collected. The average scores of knowledge, attitude, and behavior were (9.08 ± 1.49) (possible range: 0-10), (37.82 ± 3.96) (possible range: 8-40), and (35.82 ± 4.56) (possible range: 8-40), respectively, indicating that they had a better grasp of safe use of drugs. Logistic regression analysis showed that sex, age, education level, occupation, monthly household income per capita, marital status, health status, and different sources of information were the main factors affecting the knowledge and behavior of safe use of drugs of CRs. In addition to the marital status variable, other variables also have a significant impact on attitude towards safe use of drugs of CRs. CONCLUSIONS: Male sex, lower education level, lower income level, average/poor self-rated health status, and single source of drug-use information were the main factors affecting safe use of drugs based on KAP theory. The government and medical workers should carry out various forms of drug-education activities for people with different needs, encourage CRs to learn safe use of drugs, and promote safe use of drugs by CRs through diverse information sources.

More than three years' treatment response of recombinant human growth hormone in a patient with Coffin-Siris syndrome 7.

Not required for Clinical Vignette.