Off-label Research Articles

Ingestion of Fluids of the Ocular Surface Containing Eye Drops of Imidazole Derivatives-Alpha Adrenergic Receptor Agonists as Paragons.

Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.

IL-1 Inhibitors in the Treatment of Familial Mediterranean Fever: Treatment Indications and Clinical Features in a Large Real-World Cohort.

Background: The accruing evidence about the efficacy of anti-IL-1 agents in Familial Mediterranean Fever (FMF) patients led to their widespread off-label use. Therefore, identifying precise indications and clinical characteristics of IL-1i-warranting patients are important. This study investigated the clinical characteristics and treatment indications of patients with FMF requiring interleukin 1 inhibition therapy (IL-1i). Methods: Hospital records of FMF patients attending a tertiary care center at the Department of Rheumatology, University of Health Sciences, Basaksehir Cam and Sakura City Hospital were retrospectively analyzed. Data on symptoms and disease manifestations, age of symptom onset, time to diagnosis, MEFV variants, type of treatment, and their indications were collected. Results: Between June 2020 and March 2023, 312 FMF patients were identified. The mean age at the onset of symptoms was 14.0, and the mean time to diagnosis was 11.9 years. In total, 87.1% of patients were receiving colchicine monotherapy, while the remaining 11.8% warranted IL-1i. Clinical symptoms and flare manifestations did not show a significant difference between the two groups. However, patients receiving IL-1i started having symptoms at younger age (11.5 vs. 14.5, p = 0.042) and time to diagnosis was longer (18.2 vs. 11.0, p < 0.01). M694V homozygosity was more common in patients receiving IL-1i. Indications for patients receiving IL-1i were colchicine resistance (8.0%), secondary amyloidosis (5.1%), and colchicine intolerance (2.2%). Conclusions: This study shows that a subset of FMF patients, particularly those with a more severe phenotype with an earlier disease onset and M694V homozygosity, require IL-1i treatment despite the overall good efficacy and tolerability of colchicine, primarily due to colchicine resistance, intolerance, or complications such as amyloidosis.

Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning.

Drug repurposing (repositioning) is a dynamically-developing area in the search for effective therapy of infectious diseases. Repositioning existing drugs with a well-known pharmacological and toxicological profile is an attractive method for quickly discovering new therapeutic indications. The off-label use of drugs for infectious diseases requires much less capital and time, and can hasten progress in the development of new antimicrobial drugs, including antibiotics. The use of drug repositioning in searching for new therapeutic options has brought promising results for many viral infectious diseases, such as Ebola, ZIKA, Dengue, and HCV. This review describes the most favorable results for repositioned drugs for the treatment of bacterial infections. It comprises publications from various databases including PubMed and Web of Science published from 2015 to 2023. The following search keywords/strings were used: drug repositioning and/or repurposing and/or antibacterial activity and/or infectious diseases. Treatment options for infections caused by multidrug-resistant bacteria were taken into account, including methicillin-resistant staphylococci, multidrug-resistant Mycobacterium tuberculosis, or carbapenem-resistant bacteria from the Enterobacteriaceae family. It analyses the safety profiles of the included drugs and their synergistic combinations with antibiotics and discusses the potential of antibacterial drugs with antiparasitic, anticancer, antipsychotic effects, and those used in metabolic diseases. Drug repositioning may be an effective response to public health threats related to the spread of multidrug-resistant bacterial strains and the growing antibiotic resistance of microorganisms.

Evaluation of off-label rapamycin use on oral health.

Rapamycin (sirolimus) is an FDA approved drug with immune modulating properties that is being prescribed off-label in adults as a preventative therapy to maintain healthspan. We recently published one of the first reports on 333 adults with a history of off-label rapamycin use. Along with presenting evidence that rapamycin can be used safely in adults of normal health status, we discovered that about 26% of rapamycin users also reported oral health changes. Given the recent evidence highlighting the potential benefits of rapamycin and its derivatives in enhancing oral health, we conducted a secondary data analysis to profile the oral health of off-label rapamycin users, the true incidence of mouth sores, and present specific case studies of periodontal bone loss quantification using an FDA-approved artificial intelligence platform. Contrary to expected findings and previous literature, dimensions of rapamycin usage (such as length of use, dosage, and interval) were not found to be related to the incidence of mouth ulcers in rapamycin users. Notably, among rapamycin users, the most deleterious forms of ulcers were found to be infrequent and not statistically linked to rapamycin usage, with most rapamycin users having a common transient form of mouth ulcers. Additionally, we describe the general oral health outcomes of off-label rapamycin users and provide recommendations for individuals engaging in off-label rapamycin to be regularly checked by a dentist or an oral health care provider. This report was limited by being a secondary data analysis taken from survey data that focused on a more holistic health model. Future studies will use a focused survey that collects data on more dimensions of oral health outcomes while including questions on oral health for non-rapamycin-using participants.

Role of IL-23 inhibitors including risankizumab and guselkumab in the treatment of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare and chronic inflammatory dermatologic condition characterized by hyperkeratotic salmon-colored plaques and palmoplantar keratoderma. Traditional therapeutic modalities have shown limited efficacy and often entail potential adverse effects, highlighting the need for alternative treatment options. Our review aims to summarize the current evidence on the off-label use of IL-23 inhibitors, risankizumab and guselkumab, in the treatment of PRP. These biologic agents have been approved for psoriasis, and their potential role in managing PRP has recently garnered interest. We conducted a comprehensive literature search on PubMed and Scopus databases, identifying relevant studies published in English up to June 2023 following PRISMA guidelines. A total of 10 studies were selected for data extraction and review. Results from the selected studies demonstrated encouraging outcomes with both risankizumab and guselkumab in managing PRP. Among 11 patients treated with risankizumab, 10 showed notable improvements in various disease manifestations, including pruritus, erythema, and affected body surface area. DLQI scores and BSA percentages reported a significant improvement before and after risankizumab treatment (p = 0.0322; p = 0.0216). However, two cases also reported symptom aggravation or even disease worsening. Patients treated with guselkumab exhibited ultimate improvement in all five cases, with complete clearance in three out of five cases. DLQI and BSA percentages also reported significant improvement with treatment with guselkumab (p = 0.0172; p < 0.0001). While most cases demonstrated positive outcomes, there were isolated instances of worsening symptoms, emphasizing the need for caution and further investigation. Further research with larger sample sizes and longer follow-up periods is necessary to establish the efficacy, optimal dosing, and long-term safety of risankizumab and guselkumab in treating PRP. Overall, we provide valuable insights into the potential use of IL-23 inhibitors, risankizumab, and guselkumab, as promising treatment options for PRP. These biologics have shown efficacy in improving symptoms in treatment-resistant cases, offering new avenues for clinicians to explore in the treatment of PRP.

Pediatric Pharmacology for the Primary Care Provider: Advances and Limitations.

Despite >1 in 5 children taking prescription drugs in the United States, off-label drug use is common. To increase the study of drugs in children, regulatory bodies have enacted legislation to incentivize and require pediatric drug studies. As a result of this legislation, novel trial approaches, and an increase in personnel with pediatric expertise, there have been numerous advancements in pediatric drug development. With this review, we aim to highlight developments in pediatric pharmacology over the past 6 years for the most common disease processes that may be treated pharmacologically by the pediatric primary care provider. Using information extracted from label changes between 2018 and 2023, the published literature, and Clinicaltrials.gov, we discuss advances across multiple therapeutic areas relevant to the pediatric primary care provider, including asthma, obesity and related disorders, mental health disorders, infections, and dermatologic conditions. We highlight instances in which new drugs have been developed on the basis of a deeper mechanistic understanding of illness and instances in which labels have been expanded in older drugs on the basis of newly available data. We then consider additional factors that affect pediatric drug use, including cost and nonpharmacologic therapies. Although there is work to be done, efforts focused on pediatric-specific drug development will increase the availability of evidence-based, labeled guidance for commonly prescribed drugs and improve outcomes through the safe and effective use of drugs in children.

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D

BackgroundIn a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.MethodsIn this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.ResultsA total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.ConclusionsThe combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.)

Alteplase- and Tenecteplase-Related Errors and Risk Mitigation Strategies in the Treatment of Acute Ischemic Stroke: A Study of Event Reports From 52 Hospitals

Background: Alteplase and tenecteplase are thrombolytic agents used to treat patients with acute ischemic stroke (AIS). Despite the convenient bolus dosing of tenecteplase, its off-label use for AIS creates new patient safety challenges that are understudied. Methods: The study was conducted in two parts. In Part I, we queried the Pennsylvania Patient Safety Reporting System (PA-PSRS) database for event reports involving alteplase and tenecteplase that were submitted between 2017 and 2022. Based on results from Part I, in Part II we narrowed the query to reports submitted in 2021–2022 and applied inclusion criteria to identify reports that described a medication error involving the use of alteplase or tenecteplase to treat AIS. In Part II, all reports were reviewed and coded for stages of the medication-use process, associated factors, and event type. Results: Part I results (N=858) showed a decrease in reports of alteplase events and an increase in reports of tenecteplase events. In Part II (N=92), 52% of reports involved alteplase and 48% involved tenecteplase. Wrong dose was the most frequently coded event type for both medications at a combined 48%. Several tenecteplase-related events were attributed to unfamiliarity with the medication, confusion between indications, and incorrect use of the electronic health record (EHR) or failure to use the EHR, whereas many errors unique to alteplase occurred during the multistep calculation, preparation, and administration processes. Conclusions: Safety events involving alteplase and tenecteplase in the treatment of AIS are diverse. We present a list of potential strategies to prevent and mitigate errors involving these high-alert medications and encourage providers to adopt those that are meaningful to their workflow and practice setting.

Advancing perspectives on the off-label use of anticancer drugs: an updated classification and exploration of categories.

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the off-label use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the off-label use of antitumor drugs.

Offering extended use of the contraceptive implant via an implementation science framework: a qualitative study of clinicians’ perceived barriers and facilitators

BackgroundThe etonogestrel contraceptive implant is currently approved by the United States Food and Drug Administration (FDA) for the prevention of pregnancy up to 3 years. However, studies that suggest efficacy up to 5 years. There is little information on the prevalence of extended use and the factors that influence clinicians in offering extended use. We investigated clinician perspectives on the barriers and facilitators to offering extended use of the contraceptive implant.MethodsUsing the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured qualitative interviews. Participants were recruited from a nationwide survey study of reproductive health clinicians on their knowledge and perspective of extended use of the contraceptive implant. To optimize the diversity of perspectives, we purposefully sampled participants from this study. We used content analysis and consensual qualitative research methods to inform our coding and data analysis. Themes arose deductively and inductively.ResultsWe interviewed 20 clinicians including advance practice clinicians, family medicine physicians, obstetrician/gynecologist and complex family planning sub-specialists. Themes regarding barriers and facilitators to extended use of the contraceptive implant emerged. Barriers included the FDA approval for 3 years and clinician concern about liability in the context of off-label use of the contraceptive implant. Educational materials and a champion of extended use were facilitators.ConclusionsThere is opportunity to expand access to extended use of the contraceptive implant by developing educational materials for clinicians and patients, identifying a champion of extended use, and providing information on extended use prior to replacement appointments at 3 years.

Sofosbuvir Off-label Treatment of Yellow Fever Patients During an Outbreak in Brazil, 2018: A Cohort Study.

We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400 mg sofosbuvir from 4 to 10 days post-symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post-symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment.

Off-label use of fam-trastuzumab deruxtecan-nxki with early activity in a cohort of patients with desmoplastic small round cell tumor.

11584 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma occurring predominantly in pediatric, adolescent and young adult biologic males, and is molecularly characterized by the pathognomonic EWSR1-WT1 fusion. Despite aggressive multi-modality therapy outcomes for those with DSRCT remain poor, and more effective therapies are urgently required. Prior pre-clinical data and transcriptomic analyses of DSRCT patients has suggested the relevance of the ERBB2 pathway in this disease, prompting the off-label use of fam-trastuzumab deruxtecan-nxki (T-DXd) in the treatment of patients of DSRCT patient with relapsed and refractory disease. Methods: Patients with relapsed/refractory DSRCT received T-DXd 5.4 mg/kg intravenously in 21-day cycles. Whole body PET and CT of the chest, abdomen and pelvis were used for monitoring. Response was correlated with HER2 immunohistochemistry (IHC) status and transcriptomic analysis by RNA sequencing (RNAseq) when available. Results: Seven patients received the agent, and at the time of submission 3 patients had at least one follow up imaging test after receiving between 6 and 9 cycles of T-DXd. Treatment was overall well tolerated with the only grade 3 toxicity of transaminitis (in patients with known liver metastases), which self-resolved. All other toxicities including constipation, nausea, and fatigue were grade 2 or less. All 3 patients have experienced clinical benefit including one patient with a RECIST 1.1 partial response and two patients with stable disease. Additionally, favorable responses were noted by PET imaging. Four additional patients with relapsed/refractory DSRCT have initiated off-label treatment with T-DXd and are pending imaging responses. 7/7 and 4/7 patients have available IHC and ERBB2 RNA expression data available respectively. All ERBB2 RNA expression data is elevated when compared with the median across all evaluated pediatric tumors in our institutional series. Conclusions: The use of anti-HER2 therapy in a limited and unselected group of heavily pre-treated DSRCT patients is demonstrating an early signal of activity with minimal toxicity and suggests that formal assessment as monotherapy or in other relevant combinations in clinical trials is warranted. Further correlation with IHC and RNAseq expression data may help optimize correlatives and/or generate biomarkers for future clinical trials.

SEROLOGICAL RESPONSE TO CANINE DISTEMPER VACCINATION IN WILD CAUGHT RACCOONS (PROCYON LOTOR).

Canine distemper virus (CDV) is a well-known RNA virus that affects domestic dogs and all families of wild terrestrial carnivores. Spillover infections from wildlife to domestic animals are mitigated by preventive vaccination, but there is limited information on the off-label use of veterinary vaccines for wildlife like raccoons (Procyon lotor). Twenty wild-caught raccoons were inoculated with a commercial recombinant DNA canarypox-vectored CDV vaccine, applying a regimen of two serial doses by SC route with an interval of 25-28 days between doses. The CDV serum virus neutralizing antibody (VNA) baseline titers and the postvaccination titers were measured at fixed time points. Forty percent (8/20) of the wild-caught raccoons had CDV VNA titers of 1:8 or greater upon intake, and all but a single individual were juvenile animals. Approximately one month following the first vaccine dose, 8% (1/12) of raccoons seronegative at baseline had serum CDV VNA titers of 1:24 or greater. Approximately one month following the booster vaccine dose, 67% (8/12) of raccoons seronegative at baseline had serum CDV VNA titers of 1:24 or greater. Among raccoons with CDV VNA titers greater than or equal to 1:8 at baseline, 13% (1/8) demonstrated a fourfold or greater rise in titer one month after the first vaccine dose, whereas 38% (3/8) reached the same threshold one month after the booster dose. The presence of naturally acquired CDV VNA in juvenile raccoons at the time of vaccination may have interfered with the humoral VNA response. A regimen of at least two serially administered SC vaccine doses may be immunogenic for raccoons, but further investigation of alternative routes, regimens, and CDV vaccine products is also warranted for this species.

An Issue about Off-Label-Use of Controlled Medicines: The Popularity and the Worry of Propofol— On the Legal Effects of Off-Label Use of Controlled Substance by Physicians

An Issue about Off-Label-Use of Controlled Medicines: The Popularity and the Worry of Propofol— On the Legal Effects of Off-Label Use of Controlled Substance by Physicians

Off-label use of checkpoint inhibitor (CPI) monotherapy in PD-L1–negative or unknown recurrent/metastatic head and neck cancer (R/M HNSCC).

6025 Background: The KN-048 study established that the CPI pembrolizumab with chemotherapy should be used for PD-L1 negative R/M HNSCC, while CPI monotherapy has limited efficacy (ORR 4%) in PD-L1 negative disease and should be reserved for PD-L1 positive disease. National patterns of PD-L1 testing and PD-L1 guided treatment selection are unknown. We examined PD-L1 testing rates, the use of CPI overall, and the use of CPI monotherapy in PD-L1 negative or unknown R/M HNSCC (“off-label”), and associated factors. Methods: This retrospective analysis included adult patients starting treatment for R/M HNSCC from 2019-2023 in the Flatiron Health electronic health record (EHR)-derived de-identified national database. Demographics, treatment type, and PD-L1 test results were summarized using descriptive statistics. Specifically, first-line therapy was categorized as CPI monotherapy, CPI with chemotherapy, or chemotherapy and/or cetuximab without CPI. “Off-label” use of CPI was defined as single-agent use without concurrent chemotherapy in patients with negative or unknown PD-L1. Factors associated with “off-label” use were identified using multivariable logistic regression analysis. Results: Our cohort included 3,395 patients with median age 66 (IQR 59-73), 65% White, 77% treated in a community setting, 76% with smoking history, 37% HPV positive, and 72% ECOG PS 0-1. Almost half of patients (44%) did not have a recorded PD-L1 test result; of those with known PD-L1 status (n=1886), distribution of combined positive score (CPS) 0, 1-19, and 20 was 19%, 41%, and 40%, respectively. The most common frontline treatment was CPI monotherapy (43%), followed by chemotherapy/cetuximab (33%) and CPI with chemotherapy (25%). CPI monotherapy use was highly prevalent in patients aged ≥75 (54%) and with ECOG PS ≥ 2 (52%). Among the subgroup of PD-L1 negative or unknown patients (n=1831), 37% (678) received CPI monotherapy (“off-label”). Factors associated with “off-label” CPI monotherapy use included ECOG PS ≥ 2 (OR 1.3), age ≥ 75 (OR 1.3), community practice (OR 1.7), and earlier year (HR 1.2) (all p&lt;0.05). Conclusions: Most US patients with R/M HNSCC are now receiving CPI-based therapy in the frontline setting, but PD-L1 testing rates remain suboptimal. Use of CPI monotherapy in PD-L1 negative or unknown HNSCC is common, particularly in elderly patients and those with poor performance status.[Table: see text]

EXPLORING THE UNINTENDED CONSEQUENCES OF MISUSE OF WEGOVY AND OZEMPIC IN WEIGHT MANAGEMENT: A COMPREHENSIVE REVIEW

In recent years, Glucagon-Like Peptide-1 (GLP-1) receptor agonists have emerged as promising options for weight management, offering not only glycemic control benefits but also significant reductions in body weight. Among these agents, Wegovy (semaglutide) and Ozempic (semaglutide) have gained attention for their efficacy in promoting weight loss, even in individuals without diabetes. However, the off-label use of these medications for weight management raises several questions and concerns regarding their safety, efficacy, and long-term effects. This comprehensive review aims to explore the complexities of GLP-1 agonists in weight management, focusing on their mechanism of action, clinical evidence, safety profile, dosing considerations, potential interactions, and future directions.

Temporal Trends and Outcomes of Abdominal Aortic Aneurysm Care in the United States.

Endovascular aortic aneurysm repair (EVAR) has had a dynamic impact on abdominal aortic aneurysm (AAA) care, often supplanting open AAA repair (OAR). Accordingly, US AAA management is often highlighted by disparities in patient selection and guideline compliance. The purpose of this analysis was to define secular trends in AAA care. The Society for Vascular Surgery Vascular Quality Initiative was queried for all EVARs and OARs (2011-2021). End points included procedure utilization, change in mortality, patient risk profile, Society for Vascular Surgery-endorsed diameter compliance, off-label EVAR use, cross-clamp location, blood loss, in-hospital complications, and post-EVAR surveillance missingness. Linear regression was used without risk adjustment for all end points except for mortality and complications, for which logistic regression with risk adjustment was used. In all, 66 609 EVARs (elective, 85% [n=55 805] and nonelective, 15% [n=9976]) and 13 818 OARs (elective, 70% [n=9706] and nonelective, 30% [n=4081]) were analyzed. Elective EVAR:OAR ratios were increased (0.2 per year [95% CI, 0.01-0.32]), while nonelective ratios were unchanged. Elective diameter threshold noncompliance decreased for OAR (24%→17%; P=0.01) but not EVAR (mean, 37%). Low-risk patients increasingly underwent elective repairs (EVAR, +0.4%per year [95% CI, 0.2-0.6]; OAR, +0.6 points per year [95% CI, 0.2-1.0]). Off-label EVAR frequency was unchanged (mean, 39%) but intraoperative complications decreased (0.5% per year [95% CI, 0.2-0.9]). OAR complexity increased reflecting greater suprarenal cross-clamp rates (0.4% per year [95% CI, 0.1-0.8]) and blood loss (33 mL/y [95% CI, 19-47]). In-hospital complications decreased for elective (0.7% per year [95% CI, 0.4-0.9]) and nonelective EVAR (1.7% per year [95% CI, 1.1-2.3]) but not OAR (mean, 42%). A 30-day mortality was unchanged for both elective OAR (mean, 4%) and EVAR (mean, 1%). Among nonelective OARs, an increase in both 30-day (0.8% per year [95% CI, 0.1-1.5]) and 1-year mortality (0.8% per year [95% CI, 0.3-1.6]) was observed. Postoperative EVAR surveillance acquisition decreased (67%→49%), while 1-year mortality among patients without imaging was 4-fold greater (9.2% versus imaging, 2.0%; odds ratio, 4.1 [95% CI, 3.8-4.3]; P<0.0001). There has been an increase in EVAR and a corresponding reduction in OAR across the United States, despite established concerns surrounding guideline adherence, reintervention, follow-up, and cost. Although EVAR morbidity has declined, OAR complication rates remain unchanged and unexpectedly high. Opportunities remain for improving AAA care delivery, patient and procedure selection, guideline compliance, and surveillance.

Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).

e13084 Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB &gt;10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.

Heterogeneous brain distribution of bumetanide following systemic administration in rats.

Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood-brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.