Adverse Event Profile Research Articles

Peroral Endoscopic Myotomy for Achalasia Among the Elderly Population: A Systematic Review and Meta-Analysis.

Achalasia is an esophageal motility disorder associated with halting symptoms. There is conflicting evidence about the feasibility of peroral endoscopic myotomy (POEM) for achalasia among the elderly. In this meta-analysis, we sought to evaluate POEM's therapeutic safety and efficacy among elderly patients with achalasia. Major databases were searched to find articles that compared the feasibility and safety of POEM for Achalasia between 4 age groups in 2 separate comparisons: ≥75 and <75 years, and ≥65 and <65 years. Our primary outcomes of interest were to compare POEM's technical and clinical success rates. The secondary outcome was the adverse events of the procedure. A random effect model calculated pooled odds ratios with 95% CIs. Six studies were included with 290 patients ≥75 years of age and 2290 <75, 177 ≥65, and 354 younger than 65. The pooled technical success rate was 98.66% and 97.81% for patients ≥75 years of age and younger than 75, respectively. Similarly, the pooled clinical success rate was 99.01% and 97.97% for ≥75 and younger than 75, respectively. The pooled technical success rate was 99.69% and 99.84% for ≥65 and younger than 65, respectively. Similarly, the pooled clinical success rate was 95.74% and 95.31% for ≥65 and younger than 65, respectively. There was no difference in the technical and clinical success rates in both comparison groups. Also, the 2 groups had no difference in the adverse events profile of the 2 comparison groups. Our study demonstrates the feasibility and safety of POEM for achalasia among older people despite their comorbidities.

Adverse drug event profile of pharmacotherapies for alcohol use disorder: a retrospective pharmacovigilance disproportionality analysis study.

ABSTRACT Background Alcohol Use Disorder (AUD) significantly affects global health, leading to physical deterioration and impacting personal and social relationships. This study aims to evaluate the adverse event profiles (AEP) of three USFDA-approved medications for AUD, acamprosate, disulfiram, and naltrexone, using data from the USFDA Adverse Event Reporting System (AERS). Research designs and methods Reports related to acamprosate, disulfiram, and naltrexone from March 2004 to March 2024 were extracted from the USFDA AERS database. Data were verified, and disproportionality analysis was conducted using frequentist and Bayesian methods. Adverse reactions were assessed based on reporting odds ratio, proportional reporting ratio, and Bayesian measures. Outcomes such as death, life-threatening events, and hospitalization were also analyzed. Results A total of 19,177 unique reports were analyzed (naltrexone: n = 18,544; acamprosate: n = 249; disulfiram: n = 384). Common adverse reactions included hepatobiliary, nervous system, and psychiatric disorders. Disulfiram was associated with coagulopathy and drug interactions, while naltrexone was linked to injection site reactions and hypersensitivity. Naltrexone had higher mortality reports, and disulfiram had more hospitalizations. Conclusion The study underscores the diverse AEPs of these medications, highlighting the need for careful monitoring and individualized treatment to ensure safety and efficacy in managing AUD.

Adverse event profile of ocular injury associated with JAK inhibitors in patients with rheumatoid arthritis: a disproportionality analysis.

Janus kinase inhibitors (JAKIs) have been approved for the treatment of rheumatoid arthritis (RA) for several years. A recent real-world study has shown the possibility of a relationship between the occurrence of ocular adverse events (OEs) and the use of JAKIs but failed to rule out whether those OEs are related to RA. A retrospective, pharmacovigilance study using the FDA Adverse Event Reporting System to evaluate OE reports following treatment with JAK inhibitors in patients with RA from Q1 2004 to Q1 2024. we identified 3226 cases associated with JAKIs and 24,158 cases associated with TNFIs. Most of the OEs are serious cases, the age distribution was similar but the sex distribution was not balanced. The OEs with top 10 ROR values in TNFIs had no detectable signal in JAKIs, and the time of onset of OEs also shows difference. Besides, far fewer OE were reported for baricitinib than for the other JAKIs. Different types of JAKIs are associated with special types of OEs and differ in time of onset compared with TNF inhibitors. More rigorous trials should be conducted to better understand the risk factors in JAKIs-related OEs.

Five-year outcomes with gefitinib induction and chemoradiotherapy in EGFR-mutant stage III non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study.

We previously showed the 2-year OS rate, the primary endpoint, of 90% in a phase II trial of gefitinib induction followed by chemoradiotherapy (CRT) in unresectable, stage III, EGFR-mutant, non-small-cell lung cancer (NSCLC). However, neither long-term survival data nor late-phase adverse event profiles have been presented. Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy for 8weeks. After confirming no disease progression during induction therapy, cisplatin and docetaxel on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60Gy were subsequently administered. In the enrolled twenty patients, the 5-year OS rate and median survival time were 70.0% [95% confidence interval: 45.1-85.3] and 5.5years [4.91-NE], respectively, whereas 5-year PFS rate and median PFS time were 15.0% (3.7-33.5) and 1.4years [0.69-2.29], respectively. Efficacy did not seem influenced even if radiation field was re-planed in response to the effect of gefitinib induction. As for late adverse events, pulmonary fibrosis occurred in 7 patients (35%). The median time from completion of CRT to the occurrence of the event was 245days. All were grade 1, and there was no evidence of cavitation of the lesions or chronic infections such as Aspergillus infection during the course of the disease. One case of small cell lung cancer occurred during the period. With longer follow-up time, we demonstrated favorable efficacy with tolerable toxicity profiles in the EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III, NSCLC. UMIN00005086. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000006047&type=summary&language=EjRCTs071180036 . https://jrct.niph.go.jp/latest-detail/jRCTs071180036.

Results of a multicenter retrospective cohort study evaluating the safety and efficacy of FTD/TPI plus ramucirumab in advanced gastric cancer (HGCSG2302).

351 Background: In advanced gastric cancer, trifluridine/tipiracil (FTD/TPI) is one of the standard treatments for later-line chemotherapy. Ramucirumab (RAM), an anti-VEGFR-2 monoclonal antibody, has shown promising efficacy in combination with FTD/TPI in phase II studies conducted in Japan, suggesting that this combination could improve treatment outcomes. However, there remains a paucity of real-world clinical data comparing the efficacy and safety of FTD/TPI monotherapy and FTD/TPI plus RAM combination therapy in general clinical practice. Methods: This retrospective analysis to evaluate safety and efficacy included patients with gastric cancer who were received FTD/TPI plus RAM combination therapy or FTD/TPI monotherapy between August 2019 and March 2023 at 21 institutions. Results: 164 patients were analyzed, 38 patients in the RAM combination group and 126 in the FTD/TPI monotherapy group. The distribution of treatment lines (third/fourth/fifth) was 10/13/15 in the RAM group and 26/54/46 in the monotherapy group, respectively. RAM had been previously administered to 34 patients (89.5%) in the RAM group. Objective response rate and disease control rate were 11.1% / 55.6% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the RAM group and 5.5% /38.5% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the monotherapy group, respectively. Median progression-free survival (PFS) was 3.5 months in the RAM group and 2.1 months in the monotherapy group (HR 0.69, 95% C.I. 0.49-1.02, p=0.06), respectively. Median overall survival (OS) was 8.4 months in the RAM group and 5.8 months in the monotherapy group (HR 0.82, 95% C.I. 0.54-1.25, p=0.350), respectively. Grade 3 neutropenia was reported in 48.6%/52.4% (p=0.707), and there were no significant differences in other adverse event profiles between the two groups. Additionally, in the RAM group, a comparison between patients receiving standard dosing (2 weeks on/2 weeks off; n=7) and those on biweekly dosing (1 week on/1 week off; n=24) showed no notable differences in efficacy or safety. Conclusions: FTD/TPI plus RAM combination therapy showed a trend toward prolonged PFS compared to FTD/TPI monotherapy, but no significant difference in OS.

Impact of UGT1A1*28 polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3.

717 Background: SN-38, the active metabolite of irinotecan, is cleared by the liver enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and biliary excretion. UGT1A1*28 (genotype 7/7) homozygosity is associated with reduced activity of UGT1A1 and a recommendation for dose adjustment of non-liposomal irinotecan, a component of the FOLFIRINOX regimen. In this post-hoc analysis, we analyzed the impact of UGT1A1*28 homozygosity on the incidence and profile of treatment-emergent adverse events (TEAEs) among patients enrolled in NAPOLI 3 (NCT04083235). Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. UGT1A1*28 status was evaluated in all patients before enrollment. All patients, regardless of UGT1A1*28 status, received the full starting dose of liposomal irinotecan and followed the same dose reduction rules. This exploratory analysis of TEAEs by UGT1A1*28 status was descriptive; statistical analyses were not performed. Results: Overall, 83 patients (11.0%) were homozygous for UGT1A1*28 , among whom the incidence of TEAEs was similar to patients with non-homozygous status (Table). The most frequently reported TEAEs (≥ 40%) among the homozygous group (vs the overall NAPOLI 3 population) were diarrhea (59.0% vs 70.5%), nausea (56.4% vs 59.5%), vomiting (46.2% vs 39.7%) and anemia (41.0% vs 26.2%) in the NALIRIFOX arm and nausea (45.5% vs 42.7%), fatigue (45.5% vs 37.7%), diarrhea (45.5% vs 36.7%) and anemia (40.9% vs 40.4%) in the Gem+NabP arm. Conclusions: The incidence of TEAEs, including TEAEs leading to death, was similar between patients with homozygous and non-homozygous UGT1A1*28 status, in both treatment arms. The profile of TEAEs was consistent with that of the overall NAPOLI 3 population. UGT1A1*28 status did not substantially influence the safety profile or subsequent need for dose reductions of liposomal irinotecan in NAPOLI 3. Clinical trial information: NCT04083235 . UGT1A1*28 homozygous UGT1A1*28 non-homozygous TEAE, n (%) NALIRIFOX (n = 39) Gem+NabP (n = 44) NALIRIFOX (n = 328) Gem+NabP (n = 331) Any 39 (100.0) 44 (100.0) 327 (99.7) 328 (99.1) Related to any drug 39 (100.0) 41 (93.2) 310 (94.5) 308 (93.1) Grade ≥ 3 31 (79.5) 34 (77.3) 288 (87.8) 288 (87.0) Serious 24 (61.5) 24 (54.5) 176 (53.7) 168 (50.8) Leading to treatment discontinuation 15 (38.5) 10 (22.7) 103 (31.4) 100 (30.2) Leading to dose reduction of any drug 23 (59.0) 14 (31.8) 182 (55.5) 174 (52.6) Leading to interruption of any drug 1 (2.6) 1 (2.3) 15 (4.6) 3 (0.9) Leading to death 2 (5.1) 4 (9.1) 20 (6.1) 19 (5.7)

A real-world pharmacovigilance analysis for Demethylation drug: findings from the FDA adverse event reporting database.

The real-world safety profiles of the demethylating agents Azacitidine and Decitabine remain inadequately characterized despite their widespread clinical use. Both drugs are extensively employed for the treatment of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This study aims to evaluate their adverse event (AE) profiles by leveraging data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. All adverse drug event (ADE) data related to Azacitidine and Decitabine were collected from the FAERS database from its inception through the second quarter of 2024 (Q2). After standardizing the data, four disproportionality methods were applied to evaluate the association between Azacitidine, Decitabine, and ADEs. The Weibull shape parameter (WSP) was used to analyze the time-to-onset curves. Among the 15,538 ADEs where Azacitidine was the primary suspect drug, a total of 439 preferred terms (PTs) and two system organ classes (SOCs) showed significant disproportionality across all four algorithms. These SOCs included INFECTIONS AND INFESTATIONS (n=7328, ROR 3.78) and BLOOD AND LYMPHATIC SYSTEM DISORDERS (n=5613, ROR 8.92). Compared with the Azacitidine label, 52 previously unreported ADEs were identified at the PT level. Among the 3,064 ADEs where Decitabine was the primary suspect drug, a total of 200 PTs and two SOCs exhibited significant disproportionality across all four algorithms. These SOCs included BLOOD AND LYMPHATIC SYSTEM DISORDERS (n=1284, ROR 6.53) and SURGICAL AND MEDICAL PROCEDURES (n=571, ROR 3.41). Compared with the Decitabine label, 29 previously unreported ADEs were identified at the PT level. Furthermore, the Bayesian Confidence Propagation Neural Network (BCPNN) algorithm revealed that the highest IC025 values for both Azacitidine and Decitabine were concentrated in SOCs related to benign, malignant, and unspecified tumors. In summary, using the FAERS database, we compared the real-world safety profiles of two demethylating agents, Azacitidine and Decitabine. The results indicate that adverse drug reactions (ADRs) related to these two agents are concentrated in the hematologic, respiratory, circulatory, and digestive systems, as well as in neoplasms of unspecified nature, warranting close clinical attention.

Anatomical and Functional Outcomes of Heavy Silicone Oil (Oxane® HD and Densiron® 68) in Complex Primary Rhegmatogenous Retinal Detachment.

To evaluate the efficacy of heavy silicone oils (HSO) as endotamponades in the repair of primary complex rhegmatogenous retinal detachment (RRD). This retrospective, single-centre, non-randomised study included 82 eyes of 82 patients with primary macular-off RRD associated with inferior proliferative vitreoretinopathy. Each eye was treated with one of two HSO tamponades: Oxane® HD or Densiron® 68. Study outcomes were primary and final success rates, final logMAR gain and postoperative complications. The final outcome was based on 12-month follow-up. Of the 82 eyes, 45 were treated with Oxane HD and 37 with Densiron 68. There were no significant differences in demographic and clinical characteristics between the groups. The primary and final surgical success rates were 66.6% and 75.7% for Oxane HD and 75.6% and 81% for Densiron 68, respectively; these differences were not statistically significant. In addition, the final logMAR gain was 0.36 ± 0.51 (median 0.2) in the Oxane HD group and 0.57 ± 0.58 (median 0.5) in the Densiron 68 group (p = 0.027). Complication rates were similar between groups (p > 0.05). Our study suggests that HSOs may be an effective alternative for suitable patients in primary complex RRD cases, demonstrating high anatomical success and a low adverse event profile.

P-82. Doxycycline versus other oral antibiotics for the treatment of gram-positive bone and joint infections

Abstract Background The OVIVA trial demonstrated oral agents with high bioavailability after one week of IV treatment is non-inferior in treatment of bone and joint infections (BJI) compared to continued IV therapy. Oral therapy significantly reduced rates of IV catheter complications and hospital length of stay. Certain highly bioavailable oral options with coverage for gram-positive organisms were well studied in this phase III trial, such as linezolid (LZD) and trimethoprim/sulfamethoxazole (TMP/SMX), with doxycycline representing a small proportion. LZD and TMP/SMX exceeded their respective Clinical and Laboratory Standards Institute (CLSI) breakpoints and MIC90 values in the bone. Doxycycline achieves concentrations of 3 mcg/mL in the bone but may not reach upper concentrations of susceptibility per the CLSI breakpoint (≤ 4 mcg/mL). LZD and TMP/SMX penetrate the bone well, but adverse effects may make prolonged therapy difficult to tolerate compared to doxycycline. Methods A retrospective chart review was conducted of individuals ≥ 18 years prescribed doxycycline or either LZD or TMP/SMX for the treatment of a presumed or confirmed gram-positive BJI within the Grady Health System between January 1, 2021, and June 30, 2022. Individuals were included if they were referred to an ID provider within our Transitions of Care clinic and received oral antibiotics for ≥1 week on discharge. The composite primary outcome was suggested or performed amputation, OR debridement, all-cause mortality, or re-initiation of antibiotics. Secondary outcomes include rate of primary therapy completion and incidence of adverse effects. Results 77 patients met inclusion for the study, doxycycline (n=33) and LZD or TMP/SMX (n=44). There was no significant difference in the primary outcome at 9 months between either group (10 vs 12, p=0.77). Loss to follow-up drove incompletion rates of primary antibiotic therapy in both groups. Laboratory adverse effects were more common in the LZD or TMP/SMX group compared to doxycycline. Conclusion Doxycycline may be associated with a favorable adverse effect profile compared to LZD or TMP/SMX. The efficacy of doxycycline compared to LZD or TMP/SMX should be considered exploratory with larger studies conducted to highlight its potential place in practice. Disclosures All Authors: No reported disclosures

ALLG APML5: Bioavailability and safety of oral arsenic trioxide assessed during consolidation therapy for APL.

The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in APL patients in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both intravenous and oral ATO 0.15 mg/kg/d, with exposure to oral ATO restricted to the first week in 2 of the 4 ATO cycles. The primary endpoint was bioequivalence of area under the curve from 0-24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary endpoint. The 90% confidence intervals (CI) around point estimates of the geometric means of the oral/intravenous ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral/intravenous ratios and 90% CI for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral/intravenous ratio 0.966 (0.879-1.063)). The adverse event profiles of oral and intravenous ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with intravenous ATO and offers a convenient alternative for patients with APL. Accession Number: ACTRN12616001022459.

Navigating the Therapeutic Landscape of Head and Neck Burkitt’s Lymphoma: A Comparative Analysis of Treatment Approaches and Associated Challenges.

Head and neck Burkitt lymphoma (HN-BL) requires tailored treatment strategies due to its unique anatomical location and aggressive nature. HN-BL poses distinctive diagnostic and therapeutic obstacles in contrast to its extranodal equivalents. This review comparatively analyzes current treatment approaches for HN-BL, including intensive chemotherapy regimens, radiation therapy strategies, and the emerging role of targeted therapies. We investigate the effectiveness and adverse effect profiles of these methodologies, emphasizing determinants that affect treatment choice including neoplasm stage, patient functional capacity, and the existence of comorbid conditions. Furthermore, the abstract discusses challenges in managing treatment-related complications, achieving optimal local control, and addressing the specific anatomical challenges posed by head and neck involvement. Finally, we explore areas requiring further investigation to improve outcomes and refine therapeutic strategies for this aggressive malignancy.

Abuse potential and analgesic efficacy of intravenous hydromorphone bolus administration among hospitalized patients with cancer pain: A double-blind, double dummy, randomized crossover trial.

There is much concern that opioids administered as intravenous (iv) bolus for pain relief may inadvertently increase their risk for abuse. However, there is insufficient data to support this. The authors compared the abuse liability potential, analgesic efficacy, and adverse effect profile of fast (iv push) versus slow (iv piggyback) administration of iv hydromorphone among hospitalized patients requiring iv opioids for pain. In this double-blind, double dummy, randomized, 2 × 2 crossover trial, patients with ≥4 cancer-related pain were randomly assigned to receive either iv hydromorphone 1 mg administered over 2 minutes (fast iv push) or 15 minutes (slow iv piggyback) during the first treatment period. Participants crossed over to receive the alternate treatments during the second period after a 6-hour washout period. Eighty-three eligible patients were allocated to slow-fast (42, 51%) or fast-slow (41, 49%). Both treatments produced low abuse potential scores with no difference between them (mean peak Drug Effect Questionnaire "drug liking" subscale of fast [24.00] vs. slow [24.34], p=.82). A total of 92% and 94% of slow and fast iv hydromorphone recipients, respectively, had similar improvements in pain scores over 120 minutes (odds ratio, 0.67; 95% confidence interval, 0.06-5.82, p=.65). Drowsiness was more frequent with the fast than the slow rate (50% vs. 29% at 15 minutes [p=.03] and 52% vs. 31% at 60 minutes [p=.03]). Slow iv hydromorphone infusion resulted in similar abuse liability potential and pain improvement but less sedation than fast injection. These findings, taken together, suggest that the slow infusion may be considered as a first-line modality for iv opioid administration in hospitalized patients requiring intermittent opioids for pain.

Therapeutic yield of comprehensive inpatient treatment for patients with intellectual disability and epilepsy - A prospective observational study.

In people with intellectual disability (ID), prevalence of epilepsy can be over 40-times higher than in normally intelligent people, impacting quality of life (QoL) of those affected. Patients with ID are often excluded from clinical trials, resulting in limited evidence regarding treatment. This study aimed to evaluate effects of a comprehensive inpatient treatment program on seizure outcome and QoL and to identify predictive factors for improvement in these measures. This prospective observational study included people with epilepsy (PWE) and ID (IQ < 70) who underwent comprehensive inpatient treatment in a tertiary epilepsy center. The program consisted of adjustments of anti-seizure medication (ASM) and various interventions such as occupational therapy, ergotherapy, logopedics, physiotherapy and counseling services, requiring a minimum hospital stay of 14days. Outcome was measured by the Liverpool Seizure Severity Scale (LSSS), Glasgow Epilepsy Outcome Scale (GEOS), Aberrant Behavior Checklist (ABC), and Liverpool Adverse Events Profile (LAEP), alongside global QoL (numerical rating scale; 10 best, 0 worst) by caregivers. Seizure outcome was classified as "favorable" for patients experiencing not more than one seizure per month without any seizure-related injuries in the last 2months. Data were collected within 2weeks prior to admission and 8weeks post-discharge. Wilcoxon signed rank tests and regression analysis were used to assess the effects of inpatient treatment and to identify predictive factors. A total of 65 patients (30 female, median age 32years) were included. During their hospital stays, number of ASM was reduced significantly, but not the total ASM dosage. Inpatient treatment led to a significant improvement in favorable seizure outcome (25% before admission vs. 46% after discharge; p=0.004) and ASM adverse effects (LAEP median 34.0 vs. 31.0; p=0.006). QoL ratings improved significantly post-treatment (rating scale median 4.0 vs. 6.0; p=0.0015). A significant improvement of global QoL after discharge compared to the time point before admission was independently associated with a reduction of ASM number during hospital stay (p=0.011). In general, higher global QoL after discharge was independently associated with a favorable seizure outcome (p<0.001) and lower scores for ASM adverse effects (p=0.03). In PWE and ID, a comprehensive inpatient treatment program may be helpful to reduce burden of seizures and of ASM adverse effects as well as to improve global QoL. A reduction of the number of ASM may facilitate improvement of global QoL.

Prevalence, Diagnosis, and Management of Stress Urinary Incontinence in Women: A Collaborative Review.

Stress urinary incontinence (SUI), defined as any involuntary leakage of urine associated with physical activity, remains underdiagnosed and undertreated. This review aims to provide an updated overview of the prevalence, diagnosis, and treatment of SUI in women, drawing upon recent evidence-based literature and clinical guidelines. A systematic search of the MEDLINE database was conducted to identify only the most up-to-date and relevant studies published up to February 26, 2024, including the reference ESTER systematic review. The search was limited to systematic reviews published in the preceding 1yr. Any additional included publications were limited to those published or referenced as part of the existing/current guidelines. Diagnosis of SUI involves a comprehensive assessment, including medical history, physical examination, and in some cases, invasive urodynamics. Pelvic floor muscle training emerges as a first-line management strategy, showing efficacy in symptom improvement when good educational instructions and supervision are provided. Surgical interventions with midurethral and single-incision slings offer a second-line option, although concerns regarding mesh-related complications persist with a decrease in its use. Moreover, the long-term efficacy of single-incision slings remains to be confirmed. Urethral bulking agents, colposuspension, and autologous fascial slings are existing alternatives supported by robust evidence, albeit with a different adverse event profile. Management of complicated and severe SUI remains challenging, with autologous fascial sling and artificial urinary sphincters being established treatments, but high-quality data remain lacking. Heightened awareness and accessibility to SUI treatment are imperative to address the gap between prevalence and medical care-seeking behavior. Pelvic floor muscle training and surgical interventions represent key modalities. However, a notable escalation in invasiveness and complication rates when transitioning to surgical interventions is clear and has resulted in a hesitance among patients to proceed along the treatment continuum, particularly in light of mesh-related complications. Ongoing research is necessary to optimize outcomes and ensure patient safety, particularly for complicated SUI where data on comparative effectiveness remain limited.

DOP116 Preclinical characterization of IMU-856, an orally available epigenetic modulator of gut barrier function and regeneration

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases, including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase and transcriptional regulator that targets the restoration of intestinal barrier function and regeneration of bowel epithelium without having any direct effect on the immune system. A double-blind, randomized, placebo-controlled phase 1/1b clinical trial of IMU-856 has been completed [1]. IMU-856 was shown to be safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. In Part C, a ‘proof of concept study’ in patients with celiac disease, IMU-856 demonstrated positive effects in four key dimensions of clinical outcome: protecting gut architecture, improving patients' symptoms severity, biomarker response and enhancing nutrient absorption. Methods In the presented preclinical studies, the target specificity and effects of IMU-856 on intestinal barrier function and regeneration were elucidated by in-vitro sirtuin activity assays, transepithelial electrical resistance (TEER) assays, dextran sulphate sodium (DSS)-induced colitis mouse models and gene expression analysis (bulk RNA sequencing). Moreover, potential immune suppressive effects of IMU-856 were assessed in stimulated human peripheral blood mononuclear cells (PBMCs). Multiple biomarkers related to health of intestinal epithelium and of enteric function were also assessed in preclinical studies and in the phase 1 trial. Results IMU-856 is a highly selective and potent modulator of SIRT6. In TEER assays, IMU-856 treatment enhanced the epithelial barrier recovery of Caco-2 monolayers after a destructive cytokine challenge and modulated tight junction protein levels. IMU-856 demonstrated activity in acute DSS-induced colitis models by reducing the severity of colitis, improving the mucosal architecture and preserving functional enterocytes (upregulation of enterocyte marker genes and the plasma biomarker citrulline). No effects of IMU-856 on T-cell proliferation and cytokine secretion (interferon-g (IFN-g)) were observed in human PBMCs. Conclusion IMU-856 data indicate restoration of intestinal barrier function and promotion of physiological mucosal regeneration without direct immunosuppressive effects and may therefore offer potential for the treatment of IBD and other gastrointestinal diseases with compromised barrier function.

DOP012 Promising effects of IMU-856, an orally available epigenetic modulator of barrier regeneration - biomarker findings from a Phase 1 clinical study

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. In preclinical studies, IMU-856´s mechanism of action has been shown to avoid suppression of immune cells. This could present a new approach to treat intestinal barrier function associated diseases without the serious consequences associated with many immunosuppressive therapies. Methods This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Phase 1b was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte function, intestinal integrity, nutrient absorption and general gut health were analyzed to assess the effect on the overall protection of gut architecture. Results IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. There were no systematic clinically relevant findings relative to safety and tolerability. Treatment with IMU-856 improved the mass, metabolic function and health of intestinal enterocytes as measured by nutrient uptake as well as several biomarkers for intestinal function and integrity as well as general gut health [1]. Conclusion IMU-856 is a safe, highly selective and potent epigenetic modulator, showing signals of improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.The positive effects of IMU-856 on various biomarkers for intestinal function, overall health and integrity in conjunction with the protection of gut architecture show that IMU-856 may offer extensive potential in other gastrointestinal diseases with compromised intestinal barrier function like IBD.

P0845 Safety and Adverse Events of the Adjuvanted Herpes Zoster Vaccine (Shingrix) in Inflammatory Bowel Disease Patients: A Comparison of Age Groups Under and Over 50 Years

Abstract Background This study investigates the safety profile of the adjuvanted herpes zoster (HZ) vaccine (Shingrix) in patients with inflammatory bowel disease (IBD), particularly comparing adverse events (AEs) in those under 50 years old versus those 50 and above. IBD patients, due to immune-modulating treatments, face an elevated risk for herpes zoster infection, yet data on the vaccine’s safety in this population remain limited. Methods A total of 244 IBD patients were enrolled and received the HZ vaccine. Participants were divided into two groups: those under 50 years and those aged 50 or older. Baseline demographic and clinical characteristics, including IBD type, medication history, and prior HZ infection, were collected. Post-vaccination local and systemic AEs, including any serious AEs (SAEs) and IBD-specific responses, were monitored following both doses. Results The mean age of participants was 45.3 years (range 18–78), with 146 individuals under 50 and 98 over 50. Common local AEs included injection site pain (51.2%) and redness (2.0%), with no notable age-related differences. Systemic AEs were predominantly myalgia (34.0%) and fatigue (19.3%), with the younger group (&amp;lt;50 years) experiencing significantly higher rates of myalgia (39.0%) and shivering (17.1%) compared to those aged 50 and older. Only one SAE was recorded: a disease flare-up requiring hospitalization in the older age group after the first dose. No SAEs were observed following the second dose. Conclusion The Shingrix vaccine is generally safe for IBD patients, with AE profiles consistent across age groups. While younger patients reported more systemic AEs like myalgia and shivering, there was no increase in severe or IBD-specific AEs. These results support broader immunization efforts in IBD patients, including those under 50 years.

A Real-World Data Analysis of Alglucosidase Alfa in the FDA Adverse Event Reporting System (FAERS) Database.

Alglucosidase alfa for injection is used as an enzyme replacement therapy for the treatment of Pompe disease. The safety profile of alglucosidase alfa-associated adverse events requires a comprehensive evaluation. In this study, we aimed to identify drug safety alert signals and investigate the real-world safety of alglucosidase alfa to guide clinical decision making and optimize the risk-benefit balance. The adverse event reports from the first quarter of 2006 to the fourth quarter of 2023 were selected by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The new and unexpected potential adverse event signals were detected using a disproportionality analysis, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Then, the Medical Dictionary for Regulatory Activities was used to systematically classify the results. After analyzing 16,945,027 adverse event reports, a total of 4326 cases of adverse events related to alglucosidase alfa were identified, spanning 27 system organ classes. A total of 359 preferred terms of adverse events for glucosidase alpha were detected. Pyrexia ranked first, followed by pneumonia, dyspnea, respiratory failure, and disease progression according to occurrence frequency. The top three system organ classes were general disorders and administration-site conditions (n = 2466), respiratory, thoracic, and mediastinal disorders (n = 1749), and infections and infestations (n = 1551). In addition to adverse effects mentioned in the product label, our study also discovered rare but high signal intensity adverse events such as chronic recurrent multifocal osteomyelitis. There are many adverse events associated with the clinical use of alglucosidase alfa, which should be closely monitored in the FAERS database. As the most effective enzyme replacement therapy for Pompe disease, it is crucial to closely monitor these adverse events. Ensuring patient safety while balancing drug effectiveness is particularly important.

Cardiovascular Complications of Immune Effector Cell Therapies in Pediatric Hematological and Solid Tumors.

Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR)-modified T-cell therapy, have shown efficacy in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and are being investigated for other malignancies. A common toxicity associated with IEC therapy is cytokine release syndrome (CRS), which can lead to cardiovascular decompensation due to systemic inflammation. Data are limited regarding cardiovascular adverse effects in children. This study aims to describe the cardiovascular adverse effect profile of IEC therapies in pediatric patients with hematologic and solid tumor malignancies. We retrospectively reviewed patients who received IECs directed towards various targets in patients with hematologic, solid, and brain tumor malignancies from January 2014 to June 2023 at Texas Children's Hospital. The primary end point was hypotension requiring vasoactive support and/or heart failure within 30 days of infusion. A total of 203 patients met inclusion criteria. Pretreatment echocardiogram was available for 142 (70%) pediatric patients, of whom 140 (96%) had normal baseline systolic function. Hypotension requiring vasoactive support occurred in 26 (13%) patients. Hematologic malignancy indications (p = 0.002), total body irradiation (TBI) (p = 0.002), and allogenic hematopoietic stem cell transplants (HCT) (p = 0.035) were associated with increased risk of hypotension requiring vasoactive support. Follow-up echocardiograms were available for 14 patients who met the primary end point, and all showed return to baseline within 6 months. Significant hemodynamic compromise occurred in a minority of patients treated with IEC therapies. All experiencing cardiac dysfunction had recovery of function, and there was no cardiovascular-related mortality.

Utilization of Cannabidiol in Post-Organ-Transplant Care.

Cannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy.