Safety Profile Research Articles

Upadacitinib and Cardiovascular Adverse Events in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Upadacitinib, a Janus kinase (JAK) inhibitor used in rheumatoid arthritis treatment, has prompted safety concerns due to potential cardiovascular adverse events. However, current evidence does not provide a definitive conclusion. We conducted a comprehensive systematic review of the literature up until March 15, 2024, utilizing databases like PubMed/Medline, Embase, and Cochrane CENTRAL. A meta-analysis approach was used to derive pooled odds ratios (OR) along with their 95% confidence intervals (CI) to assess the cardiovascular risk associated with upadacitinib. Publication bias was evaluated using Begg's and Egger's tests. Our meta-analysis included six studies with a total of 4,202 participants. For the 15 mg dosage of Upadacitinib, the pooled OR was 1.20 (95% CI: 0.3-4.3), indicating a nominal, non-significant increase in the risk of cardiovascular adverse events. Analysis of the 30 mg dosage presented a pooled OR of 2.37 (95% CI: 0.6-9.1), pointing to a higher, yet statistically insignificant, potential risk. The absence of publication bias was confirmed through Begg's and Egger's tests. The analysis suggests a potential heightened cardiovascular risk associated with Upadacitinib, more so with the 30 mg dosage. Nevertheless, the lack of statistical significance and the wide confidence intervals necessitate a prudent approach to these findings. Tailored treatment strategies, rigorous monitoring, and further empirical studies are crucial for refining the safety profile of upadacitinib and ensuring optimal patient outcomes.

RVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai proches)

BackgroundZaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination.MethodsIn this prospective cohort study, 2115 consenting close contacts (“proches”) of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralisation.ResultsTen percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p < 0.0001). There was strong correlation between antibody titres and virus neutralisation in day 28 samples (Spearman’s rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR.ConclusionsThese data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection whose state does not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required.

A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that α-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. α-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.

Comparative bioavailability of single-dose zavegepant during and between migraine attacks: A phase 1, randomized, open-label, fixed-sequence, two-period study.

To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non-migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response. Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine. This was a Phase 1, multicenter, open-label, randomized, single-dose, two-period, fixed-sequence, comparative bioavailability study. Participants with a history of 2-8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non-migraine period (Period 2). Blood samples were collected pre-dose and at pre-specified intervals up to 24 h post-dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration-time curve from time zero to infinity (AUC0-inf), and time of Cmax (Tmax). A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5-113.2) for Cmax and 90.1% (90% CI 70.2-115.5) for AUC0-inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9-90.8) for Cmax and 73.4% (90% CI 58.8-91.7) for AUC0-inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6-171.4) for Cmax and 157.0% (90% CI 133.6-184.5) for AUC0-inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post-dose and efficacy outcomes. Zavegepant exposure was comparable during a migraine attack and a non-migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non-migraine periods, there was a less-than-dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non-migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes.

Comparative Safety Profiles and Usage Patterns of Iodinated Contrast Media in Medical Imaging

Comparative Safety Profiles and Usage Patterns of Iodinated Contrast Media in Medical Imaging

Long-term safety of photobiomodulation exposure to beta cell line and rat islets in vitro and in vivo

This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm², from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM’s protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy.

Innovative Glucagon-Based Therapies for Obesity

Abstract Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21 (FGF21), and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities.

Safety Outcomes of Balloon Dilation Eustachian Tuboplasty in Pediatric Patients: A Follow-Up Study.

Balloon dilation eustachian tuboplasty (BDET) has gained popularity as a treatment modality for chronic eustachian tube dysfunction (ETD) in both adults and children. Although its safety and efficacy in the adult population have been well described, very few large-sample studies assessing its safety profile have been performed in the pediatric population. This study serves as a follow-up to a previously published analysis assessing the safety of BDET in the pediatric population. Retrospective chart review of 71 pediatric patients (139 ears) aged 11 ± 7 years who underwent BDET from 2019 to 2023. Medical records were reviewed from the extended postoperative period. A standardized grading scale that assesses severity of surgical complications was used. A total of five minor complications (7%) were noted. These included transient postoperative tinnitus, hyperacusis, otalgia, nausea, and epistaxis. There were no major complications requiring repeat intervention or need for imaging or hospital admission. In all cases, these symptoms had resolved in the postoperative time frame, with majority of them demonstrating complete resolution before the first postoperative visit.When combining these findings with the previously published paper by the same institution, the overall complication rate is 6.1% with 114 total patients. All complications between both papers are considered minor with no long-term effects. In this retrospective analysis, BDET is shown to be a relatively safe procedure when performed in the pediatric population. Upon review of the literature, this is the largest safety analysis of exclusively pediatric patients who underwent BDET. 4.

Surgical and Non-Surgical Approach for Tear Trough Correction: Fat Repositioning Versus Hyaluronic Acid Fillers

Objective: This paper compares two popular techniques for tear trough correction—fat repositioning and hyaluronic acid (HA) fillers—highlighting their efficacy, safety profiles, patient satisfaction, and associated complications. Methods: A narrative review of 20 studies comparing fat repositioning and HA fillers was conducted, focusing on parameters such as duration of results, volume restoration, complication rates, and patient satisfaction. Results: Fat repositioning provides long-lasting results but carries higher surgical risks compared with HA fillers. The transconjunctival approach is suitable for patients with minimal skin excess. The supraperiosteal plane allows for a quicker procedure and, despite postoperative edema and temporary irregular contouring, shows no difference in final cosmetic outcomes compared with other planes. Internal fixation reduces the risk of fat relapse and skin scarring but carries the risk of suboptimal positioning. HA fillers offer immediate, minimally invasive results but require periodic maintenance. The use of a cannula reduces the risk of vascular occlusion. Combining a high G’ filler for the midface with a low G’ with low hydrophilicity for the tear trough reduces the amount of filler needed and prolongs the results. Both surgical and non-surgical methods are effective, depending on patient needs and anatomical considerations. Conclusions: Fat repositioning is ideal for patients seeking long-term correction and are willing to undergo surgery, while HA fillers suit those preferring non-invasive treatments with customizable, short-term effects. Both techniques have pros and cons that must be matched to patient goals and conditions.

Adverse Drug Reactions and Safety Profiles in Cardiovascular Drug Therapy: A Pharmacovigilance Analysis

Aims: The purpose of the study is to identify adverse drug reactions (ADRs) and evaluate patient knowledge of the disease using the Knowledge Assessment Questionnaire (KAQ). This study was designed to compare adverse effects on Cardiovascular Drug Therapy. Adverse drug reaction (ADRs) is a major cause of mortality worldwide. The objective of the present study were a) to find out the prevalence of adverse drug reaction (ADRs) in the hospitalized patient by active surveillance, b) to study the profile of ADRs detected. (3) This study was done in superspecialty hospital Netaji Subhash Chandra Bose medical college &amp; Hospital, Jabalpur, for three month study. Methodology: This study was Pharmacovigilance group, belonging to department of cardiology at Netajisubhash Chandra bose medical college, Jabalpur M.P. (5) Total number of patients taken for study was 90 in number. Results and Conclusion: Total 90 subjects were recruited in the study. Drug used for their co morbidities to find out ADRs in which maximum ADRs found in chronic rheumatoid heart diseases, for this diseases patient took in two combination mainly Digoxin with Clopidogrel (47.36%) and another were with atorvastatin, spironolactone and warfarin (47.30% ADRs Adverse drug reactions on particular body system were mostly observed on CNS (32.14% ADRs). According to Naranjonaranjo causality assessment scale applied to this study illustrates that the maximum possible and probable adverse drug reaction were shown on Furosemide as well as for Digoxin and Spironolactone.

Cardiac adverse events associated with statins in myocardial infarction patients: a pharmacovigilance analysis of the FDA Adverse Event Reporting System.

Despite the advent of new pharmacotherapies, statins remain a cornerstone in the secondary prevention of myocardial infarction (MI). However, the cardiac adverse events (AEs) linked to statins are not well-documented. This pharmacovigilance study used data from the FDA Adverse Event Reporting System (FAERS) to investigate the association between statin use and cardiac AEs in MI patients. Reports from the FAERS database (2004-2023) identifying statins as the primary suspect in MI patients were analyzed. The study evaluated seven types of statins: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Disproportionality analysis using four major indices, Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma-Poisson Shrinker (MGPS), was conducted to detect signals of statin-related cardiac AEs. Of the 20,346,289 reports reviewed, 150 identified statins as the primary suspect drug in MI patients. The most common cardiac AEs were recurrent MI (50 reports), acute MI (14 reports), followed by tachycardia (10), angina pectoris (8), coronary artery occlusion (6), cardiac failure (6), and arrhythmia (6). The analysis revealed no significant signals of statin-induced cardiac AEs. The findings confirm that statin use in MI patients does not significantly increase the risk of cardiac adverse effects, supporting their safety profile in this context.

Nonclinical Similarity of the Biosimilar Candidate ABP 938 with Aflibercept Reference Product.

ABP 938 is being developed as a biosimilar to Eylea® (aflibercept reference product [RP]), an anti-vascular endothelial growth factor (VEGF) drug used in the management of retinal diseases. Previously, a comparative analytical similarity assessment demonstrated that ABP 938 and aflibercept RP have the same amino acid sequence and exhibit similar higher-order structure and biological activity. The nonclinical studies described here were designed to assess the in vitro pharmacology and the in vivo pharmacokinetics (PK), toxicokinetics (TK), and safety profiles of ABP 938 compared to aflibercept RP. In vitro target-binding kinetics and affinity for VEGF-A and placental growth factor (PIGF) isoforms were evaluated using surface plasmon resonance (SPR). Effector functions were assessed by cell-based assays. PK was evaluated in a nonterminal intravitreal (IVT) ocular distribution study in rabbits. Safety was assessed in a 1-month IVT study in cynomolgus monkeys. SPR results demonstrated that ABP 938 is similar to aflibercept RP in binding kinetics and affinity for VEGF-A111, VEGF-A121, VEGF-A165, VEGF-A189, PlGF-1, and PlGF-2 isoforms. No antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity was observed with ABP 938 and aflibercept RP. Results from thenonterminal ocular distribution study in rabbits indicated that there were no meaningful differences in the distribution kinetics between intravitreally injected ABP 938 and aflibercept RP. Additionally, there was no evidence of ocular or systemic toxicity associated with IVT administration of ABP 938 in a repeat-dose, 1-month toxicology study in cynomolgus monkeys; toxicokinetic and toxicology profiles were similar to aflibercept RP. This integrated assessment of results from the in vitro pharmacology assessment and in vivo PK and TK/toxicology profiles formed the nonclinical portion of the totality of evidence demonstrating ABP938 is a biosimilar to aflibercept RP.

Valproate-induced hyperammonemic encephalopathy in neurosurgical patients: Our experience and systematic literature review.

Sodium valproate is used for the management of seizures, status epilepticus, chronic pain syndrome, bipolar, and other affective disorders. Even with an acceptable safety profile, severe idiosyncratic reactions can occur with valproate use. A rare, serious, and life-threatening side effect of valproate is valproate-induced hyperammonemic encephalopathy (VHE). We intend to analyze the clinical presentation, diagnosis, treatment options, and outcome of VHE in neurosurgical patients and review the pertinent literature on this rare sequelae. We retrospectively reviewed patients who developed VHE following valproate use, either for the treatment of epilepsy or for seizure prophylaxis in our centre. We analyzed the demographic details, clinical presentation, diagnosis, management, and outcomes. A total of four patients with a mean age of 26.3 ± 5.1 (range 19 - 32years). Valproate was prescribed for primary seizure prophylaxis in 2 patients (50%). The commonest etiology for valproate prescription was for brain tumors (3, 75%) followed by drug-refractory epilepsy (DRE) (1, 25%). None of the patients were documented to have urea cycle disorder. The mean daily prescribed dosage of valproate was 1250 ± 559mg and the mean duration of administration was 13 ± 13.3months (range 4months - 36months). The mean serum NH3 level was 136,5 ± 44.2µmol/L (range 107 - 212.8) and all patients (4, 100%) had hyperammonemia with a mortality rate of 50% (2 patients). The hyperammonemia was treated by stopping the valproate use (4, 100%) and dialysis (2, 50%). Normalization of ammonia levels led to clinical improvement in 50% (2 patients). Neurological deterioration in the postoperative period is a diagnostic challenge. VHE is a rare and life-threatening sequelae of Valproate-associated Hyperammonemia (VAH) in neurosurgical patients. A high index of suspicion is required due to its ambiguous presentation. Early diagnosis and prompt treatment can change the course of this life-threatening sequelae.

Adverse effects of monoclonal antibodies in the treatment of moderate-to-severe asthma: a narrative review

Introduction and purpose: Over the past two decades, the management of severe asthma shifted from high doses of inhaled and oral corticosteroids to targeted biologic agents. Adverse effects of treatment with monoclonal antibodies are not yet fully characterised. The aim of this paper is to provide a comprehensive review of the adverse effects of the FDA-approved monoclonal antibodies in the treatment of moderate-to-severe asthma, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, tezepelumab. Material and methods of research: A thorough literature review was performed using PubMed Web of Science and Embase, employing key words related to monoclonal antibodies, asthma and adverse effects. Description of the state of knowledge: Omalizumab and mepolizumab have black box warning on the risk of anaphylaxis. Due to scarcity of data, no causal association between the use of monoclonal antibodies and risk of malignancy can be established. The most common adverse effects of biologic agents in severe asthma include upper respiratory tract infections, nasopharyngitis and asthma worsening. Conclusions: Overall, monoclonal antibodies have a favourable safety profile, with certain risk of side effects remains present, and is variable for the different molecules. More studies of asthmatic patients treated with monoclonal antibodies are needed to spot rare adverse events and those developing over longer time.

Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial

IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a protein that serves as a transcriptional regulator of bowel epithelium regeneration. We aimed to evaluate the safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856 in healthy participants and in patients with coeliac disease. This study reports the results from a completed first-in-human, three-part, double-blind, randomised, placebo-controlled, clinical trial of IMU-856 in healthy participants and patients with coeliac disease done in Australia and New Zealand. In part A, healthy participants were enrolled in six cohorts and randomly assigned (3:1) using a block randomisation algorithm to receive single ascending doses of IMU-856 ranging from 10 mg to 160 mg or matching placebo. Based on the results from part A, three doses were selected for part B to evaluate the safety, tolerability, and pharmacokinetics of IMU-856 once daily for 14 days using the same randomisation algorithm. Part C enrolled patients with well controlled coeliac disease. Participants were centrally randomised 1:1:1 using an interactive web response system to receive either low dose or high dose of IMU-856 or placebo once daily for 28 days that included a 15-day gluten challenge starting on day 14. The primary objective was safety and tolerability of IMU-856. Safety analyses were done on all patients who received at least one dose of the study drug. The trial is registered with the ANZCTR registry (ACTRN12620000901909). Between July 27, 2020, and Oct 28, 2022, 71 healthy participants were enrolled in part A and B and assigned to either placebo (n=19) or IMU-856 (n=52). In part A and B, the IMU-856 doses were 10 mg (n=6), 20 mg (n=6), 40 mg (n=13), 80 mg (n=12), 120 mg (n=4), 160 mg (n=11). 43 patients with coeliac disease were enrolled in part C and assigned to either placebo (n=14), IMU-856 80 mg (n=14), or IMU-856 160 mg (n=15). Treatment-emergent adverse events (TEAEs) occurred in 24 (73%) of 33 participants in part A and 15 (79%) of 19 participants in part B receiving any dose of IMU-856 compared with six (50%) of 12 participants in part A and five (71%) of seven participants in part B with placebo. TEAEs were mainly mild in severity. In part C, TEAEs occured in 26 (90%) of 29 patients on any dose of IMU-856 and ten (71%) of 14 receiving placebo; the most common TEAEs with any dose of IMU-856 by preferred term were headache (13 [45%] of 29), nausea (nine [31%]), diarrhoea (eight [28%]), and abdominal distension (seven [24%]). Two serious adverse events occurred with IMU-856 treatment (one in part B [bacterial myocarditis] and one in part C [biliary colic]), both of which were unrelated to IMU-856. No dose-limiting toxicities, systematic safety laboratory changes, or deaths occurred during the study. In part C, mean decrease in villous height was -20·9 μm (SD 34·8) among patients who received IMU-856 80 mg, -22·5 μm (51·1) among those who received IMU-856 160 mg, and -60·3 μm (52·2) among those who received placebo. The favourable safety profile, along with preliminary activity, suggests that IMU-856 should be studied in future trials of coeliac disease. Immunic Australia.

Efficacy and Safety Profile of Different Schedules of Adjuvant Trastuzumab Therapy among Patients with HER2-Positive Breast Cancer: Real-World Experience from a Tertiary Cancer Center in South India

One year of adjuvant trastuzumab is the standard of care for HER2-positive breast cancer. In low–middle income countries, delivery of 1-year trastuzumab is challenging due to significant financial burden. Evidence for shorter durations of adjuvant trastuzumab is gaining popularity in this regard. In this study, we compared the effectiveness and safety of 1 year versus shorter durations of adjuvant trastuzumab practiced in our center. In total, 312 patients were included in this analysis. The median age was 52 years. More than two-thirds of patients (67.6%) had stage 2 disease and majority were hormone-receptor-positive (62.5%). The median follow-up duration was 50 months. The 4-year disease-free survival was 97.3%. The 4-year disease-free survival for shorter durations of adjuvant trastuzumab was 98% compared with 96.7% in 1-year trastuzumab therapy group. In univariate analysis, stage at diagnosis was the only factor which had statistically significant association with disease-free survival. In multivariate analysis, none of the variables were found to be predictive of survival. Two patients (0.6%) had significant left ventricular ejection fraction decline.Shorter durations of adjuvant trastuzumab have comparable 4-year disease-free survival to standard 1-year therapy and is an alternative adjuvant treatment option for HER2-positive breast cancer patients in resource-limited settings.

Clinical outcomes in patients in any phase of CML treated with ponatinib in France-Data from the TOPASE observational study.

The TOPASE study was set up to evaluate the outcomes of chronic myeloid leukaemia [CML] patients treated with ponatinib (PON) in a real-world setting in France. One hundred and twenty CML patients, 105 in chronic phase (CP), 8 in accelerated phase (AP) and 7 in blastic phase (BP) were included. Fifty-one (49%) of the CP-CML patients were in third line of treatment. The trigger for PON initiation in CP-CML was 'poor response' in 67 patients, 'poor tolerance' in 28 patients and 'response enhancement' in seven patients. The median dose at initiation was 30 mg/day [Q1; Q3 = 15; 30] in CP-CML and 45 mg/day [Q1; Q3 = 30; 45] in AP/BP-CML. Of 98 CP-CML evaluable patients, 72 (73.5%) were considered as responders (MMR) at one time point at least once, especially for those in second line of treatment and/or presenting a T315I mutation. Ninety-six of 120 (80%) patients reported at least one adverse event. An arterial occlusive event (AOE) was reported in 11 patients (9.2%). Thus, these real-life data confirm the potency of ponatinib in resistant or intolerant patients with an acceptable safety profile in non-selected patients. NCT number: NCT04048564.

Safety and efficacy of Angong Niuhuang Pills in patients with moderate-to-severe acute ischemic stroke (ANGONG TRIAL): A randomized double-blind placebo-controlled pilot clinical trial.

Preclinical studies have indicated that Angong Niuhuang Pills (ANP) reduce cerebral infarct and edema volumes. This study aimed to investigate whether ANP safely reduces cerebral infarct and edema volumes in patients with moderate to severe acute ischemic stroke. This randomized, double-blind, placebo-controlled pilot trial included patients with acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores ranging from 10 to 20 in 17 centers in China between April 2021 and July 2022. Patients were allocated within 36 h after onset via block randomization to receive ANP or placebo (3 g/day for 5 days). The primary outcomes were changes in cerebral infarct and edema volumes after 14 days of treatment. The primary safety outcome was severe adverse events (SAEs) for 90 days. There were 57 and 60 patients in the ANP and placebo groups finally included respectively for modified intention-to-treat analysis. The median age was 66 years, and the median NIHSS score at baseline was 12. The changes in cerebral infarct volume at day 14 were 0.3mL and 0.4mL in the ANP and placebo groups, respectively (median difference: -7.1mL; interquartile range [IQR]: -18.3 to 2.3 mL, P=0.30). The changes in cerebral edema volume of the ANP and placebo groups on day 14 were 11.4mL and 4.0mL, respectively (median difference: 3.0 mL, IQR: -1.3 to 9.9 mL, P=0.15). The rates of SAE within 90 days were similar in the ANP (3/57, 5%) and placebo (7/60, 12%) groups (P=0.36). Changes in serum mercury and arsenic concentrations were comparable. In patients with large artery atherosclerosis, ANP reduced the cerebral infarct volume at 14 days (median difference: -12.3 mL; IQR: -27.7 to -0.3 mL, P=0.03). ANP showed a similar safety profile to placebo and non-significant tendency to reduce cerebral infarct volume in patients with moderate-to-severe stroke. Further studies are warranted to assess the efficacy of ANP in reducing cerebral infarcts and improving clinical prognosis. Clinicaltrials.gov, No. NCT04475328.

Comparative Efficacy and Safety of TNF-Alpha Inhibitors, IL-17 Inhibitors, and IL-23 Inhibitors in the Treatment of Moderate to Severe Psoriasis: A Systematic Review

Psoriasis is a chronic inflammatory skin disease that significantly impacts patients' quality of life. The advent of biological therapies has revolutionized the treatment landscape for moderate to severe psoriasis, offering targeted mechanisms of action with higher efficacy and improved safety profiles compared to traditional systemic treatments. This systematic review aims to evaluate and compare the efficacy and safety of three major classes of biologics: TNF-alpha inhibitors, IL-17 inhibitors, and IL-23 inhibitors. We conducted a comprehensive search of PubMed, MEDLINE, and Cochrane Library databases for randomized controlled trials (RCTs) and observational studies published between 2015 and 2023. A total of 30 studies involving over 15,000 patients were included. The primary outcomes assessed were the Psoriasis Area and Severity Index (PASI) 75, 90, and 100 response rates and safety profiles. IL-23 inhibitors demonstrated the highest efficacy, with superior PASI 90 and PASI 100 responses, followed by IL-17 inhibitors. TNF-alpha inhibitors, while effective, showed lower PASI 90 and PASI 100 response rates but had a well-established long-term safety profile. IL-17 inhibitors were associated with higher rates of candidiasis, while IL-23 inhibitors had fewer adverse events overall. This review supports the use of IL-23 inhibitors as the most effective biological therapy for moderate to severe psoriasis, with IL-17 inhibitors as a strong alternative. TNF-alpha inhibitors remain a viable option, particularly for patients with comorbid conditions where their safety profile is well-documented.

Robotic Versus Thoracoscopic Minimally Invasive Mitral Valve Surgery: A Systematic Review and Meta-Analysis of Matched Studies.

Mitral regurgitation is the most prevalent form of valvular heart disease, impacting over 24 million people globally. Robotic and thoracoscopic minimally invasive mitral valve repair (MIMR) techniques have emerged as viable alternatives to traditional open-heart surgery. However, the comparative effectiveness and safety of these 2 approaches remain underexplored. This systematic review and meta-analysis, conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, aimed to compare robotic and thoracoscopic MIMR outcomes. A literature search was performed across PubMed, Scopus, and Embase databases to identify studies comparing these 2 surgical techniques. Eligible studies included randomized controlled trials and cohort studies. Six propensity score-matched studies and 1 retrospective cohort study, involving 11,823 patients, were included, with 5851 undergoing robotic mitral valve repair and 5972 receiving thoracoscopic MIMR. No significant differences were found in perioperative mortality [risk ratio (RR): 0.97, 95% confidence interval (CI): 0.65-1.45] or pump/clamp times. Robotic surgery was associated with longer operative times (mean difference: 33.01 minutes) and higher intraoperative transfusion rates (RR: 1.53, 95% CI: 1.07-2.18), but a lower risk of atrial fibrillation (RR: 0.89, 95% CI: 0.83-0.95). In conclusion, robotic and thoracoscopic MIMR show comparable mortality and overall safety profiles. However, robotic surgery may require longer operative times and increased transfusion needs, while reducing the risk of atrial fibrillation. Further high-quality, randomized studies are warranted to validate these findings.