Drug Administration Research Articles

Safety assessment of clomiphene: a real-world pharmacovigilance analysis from the Food and Drug Administration adverse event reporting system

ABSTRACT Background Clomiphene is widely used for the treatment of anovulatory infertility, yet there remain many unrecognized adverse events (AEs). The objective of this study is to provide a comprehensive overview of the safety profile of clomiphene. Methods The data were derived from the first quarter of 2004 to the third quarter of 2023 from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The detection of new AE signals involved the use of four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). Results A total of 16,677,289 AE reports were acquired from the FAERS database, and there were 2,620 AEs specifically reported in 720 patients following clomiphene use. The AEs encompassed 102 preferred terms (PTs) across 24 system organ classes (SOCs). Some new AEs were identified, including conjoined twins (0.5%), Potter’s syndrome (0.3%), genitalia external ambiguous (0.3%), esophageal atresia (0.6%), and anal atresia (0.3%). Conclusions Although the majority of AEs aligned with the drug instruction, some new AE signals such as conjoined twins and genitalia external ambiguous were not captured. Well-designed studies are required to demonstrate the safety of clomiphene.

Simultaneous quantification of five antiretrovirals in human tissues using ultra-high performance liquid chromatography-tandem mass spectrometry methods for therapeutic drug monitoring at the sites of action

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05–50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5–107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.

Evaluating the accuracy of Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) responses to United States Food and Drug Administration (FDA) frequently asked questions about dental amalgam

BackgroundThe use of artificial intelligence in the field of health sciences is becoming widespread. It is known that patients benefit from artificial intelligence applications on various health issues, especially after the pandemic period. One of the most important issues in this regard is the accuracy of the information provided by artificial intelligence applications.ObjectiveThe purpose of this study was to the frequently asked questions about dental amalgam, as determined by the United States Food and Drug Administration (FDA), which is one of these information resources, to Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) and to compare the content of the answers given by the application with the answers of the FDA.MethodsThe questions were directed to ChatGPT-4 on May 8th and May 16th, 2023, and the responses were recorded and compared at the word and meaning levels using ChatGPT. The answers from the FDA webpage were also recorded. The responses were compared for content similarity in “Main Idea”, “Quality Analysis”, “Common Ideas”, and “Inconsistent Ideas” between ChatGPT-4’s responses and FDA’s responses.ResultsChatGPT-4 provided similar responses at one-week intervals. In comparison with FDA guidance, it provided answers with similar information content to frequently asked questions. However, although there were some similarities in the general aspects of the recommendation regarding amalgam removal in the question, the two texts are not the same, and they offered different perspectives on the replacement of fillings.ConclusionsThe findings of this study indicate that ChatGPT-4, an artificial intelligence based application, encompasses current and accurate information regarding dental amalgam and its removal, providing it to individuals seeking access to such information. Nevertheless, we believe that numerous studies are required to assess the validity and reliability of ChatGPT-4 across diverse subjects.

A review of the toxicity of ingredients in e-cigarettes, including those ingredients having the FDA's "Generally Recognized as Safe (GRAS)" regulatory status for use in food.

Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.

Comparison of QT interval readings between smartwatch ECG combined with artificial intelligence and 12-lead ECG in subjects hospitalized for antiarrhythmic drug initiation and follow-up

Abstract Background/Introduction Class III antiarrhythmic drugs (AADs) are effective for the maintenance of sinus rhythm (SR) in subjects with atrial fibrillation (AF). However, several require initial hospitalization for QT interval monitoring using the 12-lead ECG. Purpose The purpose of this study was to evaluate the feasibility of using a smartwatch single lead ECG combined with a deep learning algorithm for routine QT interval determination in the context of AAD initiation. Methods A deep learning model was developed using smartwatch and Holter ECG recordings to estimate corrected QT intervals. To evaluate the performance of this model, we carried out a prospective study on subjects hospitalized for initiation of sotalol and/or dofetilide. Subjects recorded near simultaneous (maximal 2 minutes apart) smartwatch ECGs (Apple Watch Series 6) and 12-lead ECG (Mac 5500 HD ECG or GE Carescape B450) right before and 2-3 hours after drug administration twice a day for 2-3 days. Blinded double annotation followed by adjudication of disagreement provided a reference heart rhythm (NSR or AF) and QTc interval. The tangent method was used for QTc interval determination. Bland-Altman analysis was performed to assess the agreement between QTc measures. Results Fifty subjects (mean age 67.4±10.9 years, 64% male) were enrolled in the study from February 2022 to October 2022. Out of 386 monitoring visits, 321 near simultaneous pairs of ECGs were collected with a mean delay of +15.0±41.1s for the smartwatch ECG compared to the 12-lead ECG. Overall, a mean QTcF reference value of 419.9±34.0 ms was observed (435.2±38.4 ms for QTcB, r=0.83 between annotators[BL2] ). Among the 139 pairs with 12-lead ECG found in NSR, we observed a mean QTcF difference of +19.7 ms and limits of agreements equal to -21.5 ms and 60.8 ms, with AI-facilitated measurement. In comparison, a mean QTcF difference of +22.5 ms and limits of agreements equal to -23.8 ms and 68.8 ms were observed for manual readings of smartwatch ECGs instead. Conclusion(s): Our findings suggest that a smartwatch ECG deep learning approach can estimate the QT interval with a fair agreement compared to standard 12-lead monitoring during AAD initiation. This measurement method appears to be at least as accurate as manual measurements on smartwatch ECGs. With further validation, the smartwatch-based automatic detection of QT interval prolongation, could be used for a faster, safe, and extended outpatient QT interval monitoring.Bland-Altman plots

Perceptions of the Addictiveness of Low-Nicotine Cigarettes Versus Typical Cigarettes and Exposure to Tobacco Industry-Sponsored Corrective Campaign

Background In 2017, the U.S. Food and Drug Administration (FDA) announced a regulatory plan to reduce the nicotine content of cigarettes. This study examines the association of exposure to industry-sponsored corrective statements on perceptions of the addictiveness of low-nicotine cigarettes relative to typical cigarettes within the general US population. Methods The study comprised 4975 US adult respondents of the 2019 Health Information National Trends Survey (HINTS 5, Cycle 3). Multinomial logistic regression models were used to examine associations between exposure to tobacco industry corrective messages and perceptions of the addictiveness of low-nicotine cigarettes relative to typical cigarettes. Results In the overall population, 4.1% reported that low-nicotine cigarettes were much more addictive than typical cigarettes, 67.5% said they were equally addictive, while 28.4% reported they were slightly/much less addictive. Adults exposed to industry-sponsored corrective messages had higher odds of perceiving low-nicotine cigarettes as equally addictive as typical cigarettes (aOR 1.57; 95% CI, 1.13–2.19) than those who saw no corrective messages. Those exposed to the corrective messages specifically about the addictiveness of smoking and nicotine had higher odds of perceiving low-nicotine cigarettes as equally addictive as typical cigarettes (aOR, 1.73; 95% CI, 1.07–2.81) compared to those who saw no corrective message. Conclusions Our findings suggest that exposure to court-ordered tobacco industry corrective statements may have reinforced perceptions on the addictive potential of nicotine. However, study findings indicate a need for campaigns specifically tailored to address misperceptions observed in this study.

Insight into the Functional Dynamics and Challenges of Exosomes in Pharmaceutical Innovation and Precision Medicine.

Of all the numerous nanosized extracellular vesicles released by a cell, the endosomal-originated exosomes are increasingly recognized as potential therapeutics, owing to their inherent stability, low immunogenicity, and targeted delivery capabilities. This review critically evaluates the transformative potential of exosome-based modalities across pharmaceutical and precision medicine landscapes. Because of their precise targeted biomolecular cargo delivery, exosomes are posited as ideal candidates in drug delivery, enhancing regenerative medicine strategies, and advancing diagnostic technologies. Despite the significant market growth projections of exosome therapy, its utilization is encumbered by substantial scientific and regulatory challenges. These include the lack of universally accepted protocols for exosome isolation and the complexities associated with navigating the regulatory environment, particularly the guidelines set forth by the U.S. Food and Drug Administration (FDA). This review presents a comprehensive overview of current research trajectories aimed at addressing these impediments and discusses prospective advancements that could substantiate the clinical translation of exosomal therapies. By providing a comprehensive analysis of both the capabilities and hurdles inherent to exosome therapeutic applications, this article aims to inform and direct future research paradigms, thereby fostering the integration of exosomal systems into mainstream clinical practice.

P.024 Sex and gender reporting in clinical trials among neurological US Food and Drug Administration approvals

Background: Sex and gender are related but distinct determinants of disease, treatment response, and research reproducibility whose consideration is increasingly required for research funding. Nevertheless, the quality of sex and gender reporting in neurological randomized controlled trials (RCTs) remains unknown. Methods: This ongoing study of RCTs associated with Food and Drug Administration neurological drug approvals aims to determine the frequency of accurate reporting of RCT participants’ sex and gender. Secondary outcomes include changes in reporting over time and RCT design characteristics. Results: Preliminary analysis included 145 RCTs (153,410 participants) associated with 77 medications approved in 1985-2023, most commonly for epilepsy (19%), migraine (16%), and multiple sclerosis (16%). Sixty-six RCTs (45.5%) used sex-related terms appropriately. Nine RCTs (6.2%) reported gender accurately. Fifty-three RCTs (37%) used sex- or gender-related terms interchangeably. There are no statistically significant differences in the proportions of studies reporting sex and/or gender accurately when comparing those published until versus after 2017. No RCT reported sex or gender collection methods, definitions of sex or gender, or including sex or gender minority participants. Conclusions: Preliminary results suggest shortcomings in reporting sex and, especially, gender accurately and inclusively among neurological drug RCTs and no significant improvement thereof in recent years.

Prophylactic administration of glycopyrrolate prevents vasovagal responses induced by pulsed field ablation in patients with atrial fibrillation

Abstract Background The FarapulseTM system was the first pulsed field ablation device to receive regulatory approval. Vagal Responses (VR) during pulmonary vein isolation (PVI) with this pentaspline device are frequent and often require back-up pacing or the administration of parasympathetic drugs. Glycopirrolate (GLY) is a medication of the muscarinic anticholinergic group; its efficacy for VR prevention when administered prophylactically before PVI has never been reported. Objective To evaluate the effectiveness of prophylactic intravenous administration of GLY on VRs induced by PFA. Methods Consecutive AF patients undergoing first-time PVI with PFA via the FarapulseTM system between April and October 2023 were prospectively enrolled in 3 European centers. Prophylactic administration of GLY (0.2 mg intravenous administration before femoral vein puncture) [Group GLY(+)] was adopted based on operator’s preference. VR was defined as at least one of the following: sinus bradycardia (&amp;lt;40 beats/min), asystole (&amp;gt;6 sec), or atrioventricular block (AVB) occurring immediately after a pulsed electric field application. VRs and maximum pause duration (maximum RR interval) were determined for each PV. Temporary backup pacing was performed as per the operator's preference. Results We enrolled 141 patients [GLY(+): 64 patients; GLY(-): 77 patients] undergoing PVI with the pentaspline FarapulseTM system. Median age was 54.1 years (54.1- 70), and 76 (54%) patients were males with an average CHA2DS2-VASc Score of 1.0 (0 – 2). A total of 563 PVs, including 3 left common PVs and 2 accessory middle PVs, were successfully isolated with the FarapulseTM PFA system. There were no statistically significant differences in baseline and procedural characteristics between two groups. VRs during PVI occurred in a total of 53 (37.6%) patients. GLY administration reduced significantly the incidence of any VRs (4.7% vs 64.9%; p&amp;lt;0.001) (Figure 1A). Additionally, GLY resulted in a lower incidence of VRs during LSPV (4.7% vs 62.3%; p&amp;lt;0.001) and LIPV (1.6% vs 9.1%; p&amp;lt;0.001) (Figure 1B) isolation and the need for temporary backup pacing during LSPV (24.7% vs 1.6%; p&amp;lt;0.001) isolation. Maximum pause duration was significantly shorter in the GLY(+) group after PFA of LSPV (1195 vs 3459 sec; p&amp;lt;0.001), LIPV (1128 vs 1556 sec; p&amp;lt;0.001), RSPV (1138 vs 1607 sec; p&amp;lt;0.001) and RIPV (1103 vs 1343 sec; p&amp;lt;0.001) compared to GLY(-) group (Figure 1C). Conclusions Glycopyrrolate is highly effective in the prevention of VRs induced by PFA ablation in AF patients undergoing first-time PVI.Figure 1

Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report

BackgroundPrevious reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam.Case presentationA 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups.ConclusionRemimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia.

The effectiveness of relugolix compared with leuprorelin for preoperative therapy before laparoscopic myomectomy in premenopausal women, diagnosed with uterine fibroids: protocol for a randomized controlled study (MyLacR study)

BackgroundThe oral gonadotropin-releasing hormone antagonist relugolix, which temporarily stops menstruation, is used to treat heavy menstrual bleeding, pelvic pressure, and low back pain in women with uterine fibroids. Treatment can also help women recover from low hemoglobin levels and possibly shrink the fibroids. However, evidence of preoperative use of relugolix before laparoscopic myomectomy is limited. Nevertheless, the treatment could reduce interoperative blood loss, decrease the risk of developing postoperative anemia, and shorten the operative time. Thus, we aim to test whether 12-week preoperative treatment with relugolix (40 mg orally, once daily) is similar to or not worse than leuprorelin (one injection every 4 weeks) to reduce intraoperative blood loss.MethodsEfficacy and safety of preoperative administration of drugs will be studied in a multi-center, randomized, open-label, parallel-group, noninferiority trial enrolling premenopausal women ≥ 20 years of age, diagnosed with uterine fibroids and scheduled for laparoscopic myomectomy. Participants (n = 80) will be recruited in the clinical setting of participating institutions. The minimization method (predefined factors: presence or absence of fibroids ≥ 9 cm and the International Federation of Gynecology and Obstetrics [FIGO] type 1–5 fibroids) with randomization is used in a 1:1 allocation. Relugolix is a 40-mg oral tablet taken once a day before a meal, for 12 weeks, up to the day before surgery. Leuprorelin is a 1.88 mg, or 3.75 mg subcutaneous injection, given in three 4-week intervals during patient visits before the surgery. For the primary outcome measure of intraoperative bleeding, the blood flow is collected from the body cavity, surgical sponges, and collection bag and measured in milliliters. Secondary outcome measures are hemoglobin levels, myoma size, other surgical outcomes, and quality-of-life questionnaire responses (Kupperman Konenki Shogai Index and Uterine Fibroid Symptoms—Quality of Life).DiscussionReal-world evidence will be collected in a clinical setting to use pre-treatment with an oral gonadotropin-releasing hormone antagonist to reduce intraoperative bleeding in women who undergo laparoscopic myomectomy.Trial registrationjRCTs031210564 was registered on 19 January 2022 in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp).

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States

IntroductionNovel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective.MethodsA three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients.ResultsThe analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively.DiscussionThis study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Frequency of HLA-A*02:01 in the Brazilian population and its impact on uveal melanoma systemic treatment.

Uveal melanoma is a rare malignancy originating from extracutaneous melanocytes on the uveal layer of the eyes. The incidence varies depending on the ethnic and racial global distribution, as uveal melanoma is more frequently diagnosed in non-Hispanic White subjects when compared with Hispanic, Asian, or Black individuals. Despite all the local effective management of uveal melanoma, roughly 50% of the cases will develop distant metastases. For these cases, the historical median overall survival is around 12 months. Recently, tebentafusp became the first therapy to receive Food and Drug Administration approval following a phase 3 trial demonstrating a continued long-term benefit for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. Since 2021, high-resolution sequence-based HLA typing has been considered the gold standard for determining HLA alleles and haplotypes for the Brazilian Bone Marrow Donor Registry (REDOME) donors. To depict the HLA-A*02:01-positivity in Brazilian individuals, the REDOME database was queried out for the donors included from 2021 to 2023 and tested for HLA in high-resolution platforms. A total of 203, 44 donors were included and the frequency of the HLA-A*02:01 was 21.01%, much lower compared to the frequency in North Americans and Europeans (around 45%). Despite tebentafusp has demonstrated promising results in the treatment of uveal melanoma, the number of patients to benefit from this new approach can strongly vary by ethnic and racial issues. New strategies for the systemic treatment of advanced uveal melanoma have to be developed and tested as this disease still represents an unmet medical need.

#861 Intradialytic oxygen saturation in chronic hemodialysis patients—results from a large U.S. population

Abstract Background and Aims The study of intradialytic oxygen saturation (SO2) in hemodialysis (HD) patients is a significant yet under-explored area. This study's objective was to evaluate the epidemiological aspects of SO2 during HD. Method SO2 levels during HD were measured using the Crit-Line Monitor (CLM; Fresenius Medical Care North America, Waltham, MA), a device certified by the US Food and Drug Administration (FDA) for the measurement of hematocrit and SO2 in the extracorporeal circuit. CLM measurements were recorded at 10-second intervals and transmitted into Amazon Web Services (AWS) via Apache KAFKA, a real time streaming software. Apache KAFKA was rolled out in phased approach, started early 2021. We extracted CLM data between January 14, 2021, and July 30, 2023. CLM values with the following characteristics were deemed implausible and hence, excluded: SO2 ≤ 0 or ≥99.9; hematocrit &amp;lt; 15% or &amp;gt;60%. We computed basic statistics of SO2 for every HD session. We then excluded the sessions with the standard deviation of SO2 &amp;lt; 0.1%, an interquartile range of zero, and sessions with less than 360 SO2 measurements (i.e., less than 60 minutes of recording). Results We collected data from over 5.6 million HD sessions. After data cleaning, we retained 4.9 million HD sessions from 72,656 patients treated in 727 dialysis clinics across the US. The average duration of a session was 204.5 (±42.8) minutes. Per HD session, on average 1,227 (±257) SO2 measurements were recorded. The distribution of the number of SO2 measurements per HD session is shown in Fig. 1A. The mean of the session-level average SO2 was 88% (±15%). The distribution of session-level average SO2 is shown in Fig. 1B. The bimodal distribution of SO2 is attributed to the use of arterio-venous and central venous vascular accesses, respectively. Conclusion We collected and analysed a substantial dataset of intradialytic SO2 in a large US HD population. These data provide a rich source for future research into SO2 and its clinical correlates. Exploring intradialytic SO2 in depth will offer valuable insights to improve patient care and optimize treatment procedures.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR &amp;gt;1.1 g/g), and urinary protein excretion (% with urinary protein excretion &amp;gt;1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p &amp;lt; 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.

The Ocular Chloramphenicol Story

Chloramphenicol eye drops and ointment are the most used ocular antibiotic worldwide. Chloramphenicol was discovered in 1947 and was only the third antibiotic to successfully be produced and only the first antibiotic suitable for large-scale commercial production. By the 1950s, the drug had been developed into drop and ointment forms. The broad spectrum of anti-bacterial activity of Chloramphenicol led to widespread use. Ocular Chloramphenicol remains an important weapon in the ophthalmic armamentarium despite emergence of evidence of possible side effects in the 1970s. This is a short review of the remarkable story of the discovery, development and tribulations of ocular Chloramphenicol. Keywords: History; Chloramphenicol Abbreviations: FDA: Food and Drug Administration

#1790 Metformin versus standard of care in slowing progression of autosomal dominant polycystic kidney disease and correlation with total kidney volume

Abstract Background and Aims Autosomal dominant kidney disease (ADPKD) is the most common monogenic disorder leading to renal failure with very limited therapeutic options. Apart from lifestyle modifications and control of hypertension, tolvaptan is the only Food and Drug Administration (FDA) approved disease modifying drug. Although, it has proven therapeutic benefit in slowing disease progression in high risk Mayo Class (Mayo Class 1C-E), the aquaretic potential, potential hepatotoxicity and the cost limits its widespread use especially in resource constrained country. Metformin has been shown to be effective in ADPKD in preclinical studies and is also well tolerated by the general population. We planned this study to assess the efficacy and safety of metformin in non diabetic ADPKD patients. Method Our study is a prospective, randomized controlled, open labelled clinical trial of 52 non diabetic adults 18 to 60 years of age with typical ADPKD, estimated glomerular filtration rate (eGFR) &amp;gt; 45 ml/min/m2 and no risk factors of rapid progression. Participants were randomized in a 1:1 ratio by a computer-generated random number table into Metformin + standard of care group (Metformin arm) and standard of care group (Placebo arm). Primary outcome of the study was to evaluate the effects of metformin versus placebo arm on the percentage and absolute change in eGFR over 6-month period. Secondary outcomes were to study the effect of metformin versus placebo arm on the percentage and absolute change in height adjusted total kidney volume (htTKV ml/m) at 6 months, to evaluate the effect of baseline plasma copeptin levels with percentage change in htTKV and eGFR over 6 months, to evaluate metformin tolerability, to evaluate the effects of metformin versus placebo on the changes in body weight, BMI, blood pressure and urine protein excretion at 6 months period. Results Mean (SD) age of the cohort was 37.15 (10.16) years with half of them being females. The mean (SD) baseline htTKV and eGFR was 335.67 (153.3) ml/m and 100.23 (25.95) ml/min/m2. Clinical exome sequencing was available in 9 (17.3%) patients of which two third had PKD1 mutation. Baseline characteristics were distributed equally across randomized groups. Baseline proteinuria was significantly higher in the Metformin arm (p = 0.014). The eGFR difference and percentage change in eGFR was not different between the groups at 6 months (p = 0.535, 0.483). There was no statistically significant difference in htTKV difference and percentage change in htTKV at 6 months between the groups although increase in htTKV was numerically smaller in the metformin group (p = 0.769, 0.805). Blood pressure, weight, body mass index (BMI) and proteinuria also did not differ between two groups. Half of the cohort tolerated the maximum dose of metformin. Around 2/3rd patients reported adverse effects most commonly asthenia. There was no lactic acidosis or significant gastrointestinal side effects as assessed by gastrointestinal rating scale (GSRS) scale. Baseline copeptin levels did not correlate with eGFR or htTKV difference at 6 months. Conclusion Metformin appears to be safe and tolerable in non diabetic ADPKD patients over 6 months. However larger clinical trials are needed to conclude regarding the efficacy in terms of eGFR decline or htTKV progression.

Utilizing fMRI to Guide TMS Targets: the Reliability and Sensitivity of fMRI Metrics at 3T and 1.5T.

US Food and Drug Administration (FDA) cleared a Transcranial Magnetic Stimulation (TMS) system with functional Magnetic Resonance Imaging-guided (fMRI) individualized treatment protocol for major depressive disorder, which employs resting state-fMRI (RS-fMRI) functional connectivity (FC) to pinpoint the target individually to increase the accuracy and effeteness of the stimulation. Furthermore, task activation-guided TMS, as well as the use of RS-fMRI local metrics for targeted the specific abnormal brain regions, are considered a precise scheme for TMS targeting. Since 1.5T MRI is more available in hospitals, systematic evaluation of the test-retest reliability and sensitivity of fMRI metrics on 1.5T and 3T MRI may provide reference for the application of fMRI-guided individualized-precise TMS stimulation. Twenty participants underwent three RS-fMRI scans and one scan of finger-tapping task fMRI with self-initiated (SI) and visual-guided (VG) conditions at both 3T and 1.5T. Then the location reliability derived by FC (with three seed regions) and peak activation were assessed by intra-individual distance. The test-retest reliability and sensitivity of five RS-fMRI local metrics were evaluated using intra-class correlation and effect size, separately. The intra-individual distance of peak activation location between 1.5T and 3T was 15.8mm and 19mm for two conditions, respectively. The intra-individual distance for the FC derived targets at 1.5T was 9.6-31.2mm, compared to that of 3T (7.6-31.1mm). The test-retest reliability and sensitivity of RS-fMRI local metrics showed similar trends on 1.5T and 3T. These findings hasten the application of fMRI-guided individualized TMS treatment in clinical practice.

Iridium(Ir) decorated silicon Carbide (SiC) nanosheet as a promising sensitive material for detection of γ-Hydroxybutyric acid drug based on the DFT approach

The Food and Drug Administration (FDA) has banned gamma-Hydroxybutyric acid (HBA), which is widely utilised for drug-facilitated sexual assaults across the world. As a result, it is crucial for law enforcement and drug organisations to detect HBA in biological settings. There has been substantial interest in 2D chemical nanosensors for gaseous and biological molecule detection. This paper studied the sensing performance of bare and Ir-decorated SiC nanosheets for HBA detection through the TPSS density functional. The bare SiC nanosheets were found to have insignificant responsiveness to HBA (almost 7.3 at 298 K) due to their small binding energy with the drug molecules (−0.26 eV). The Ir-decorated SiC nanosheets, however, showed superb performance in adsorbing HBA on an Si–C bond, with a binding energy of −2.54 eV. The Ir-decorated SiC nanosheets enabled strong HBA adsorption (binding energy = −1.35 eV). Therefore, the decoration of SiC sheets with Ir atoms remarkably enhanced their responsiveness to HBA molecules from 7.3 to 495.4. The recovery time for the desorption of HBA molecules from the surface of the Ir-decorated SiC nanosheets was estimated to be 1.09 s. It was concluded that Ir-decorated SiC nanosheets are a promising nanosensor to detect HBA.

Amyloid‐β in Alzheimer's disease: Structure, toxicity, distribution, treatment, and prospects

AbstractAmyloid‐β (Aβ) is a pivotal biomarker in Alzheimer's disease (AD), attracting considerable attention from numerous researchers. There is uncertainty regarding whether clearing Aβ is beneficial or harmful to cognitive function. This question has been a central topic of research, especially given the lack of success in developing Aβ‐targeted drugs for AD. However, with the Food and Drug Administration's approval of Lecanemab as the first anti‐Aβ medication in July 2023, there is a significant shift in perspective on the potential of Aβ as a therapeutic target for AD. In light of this advancement, this review aims to illustrate and consolidate the molecular structural attributes and pathological ramifications of Aβ. Furthermore, it elucidates the determinants influencing its expression levels while delineating the gamut of extant Aβ‐targeted pharmacotherapies that have been subjected to clinical or preclinical evaluation. Subsequently, a comprehensive analysis is presented, dissecting the research landscape of Aβ across the domains above, culminating in the presentation of informed perspectives. Concluding reflections contemplate the supplementary advantages conferred by nanoparticle constructs, conceptualized within the framework of multivalent theory, within the milieu of AD diagnosis and therapeutic intervention, supplementing conventional modalities.