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Schizophrenia Research Jun 2024Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational...
Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.
PubMed: 38943928
DOI: 10.1016/j.schres.2024.06.017 -
The Journal of Clinical Endocrinology... Jun 2024There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid...
BACKGROUND
There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multi-kinase inhibitors. This multi-center trial evaluated sapanisertib, a next generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC.
METHODS
A safety run-in phase I was followed by non-randomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. Primary endpoint was proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints.
RESULTS
Forty-six patients (20 ATC; 26 DTC) were enrolled including 40 (18 ATC; 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent (2/18, 95% C.I.: 1.4-34.7%) of patients with ATC were progression-free at 4 months, 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% C.I.: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment related adverse events occurred in 30% of patients who received the phase II dose, most common being anorexia, nausea, diarrhea, fatigue, skin rash and hyperglycemia. Genomic alterations in the PI3 K/AKT/mTOR pathway were not associated with response or PFS.
CONCLUSIONS
Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC, and did not show clinically meaningfully activity. Clinical trials with alternative therapeutic strategies are needed.
CLINICAL TRIAL REGISTRATION
NCT02244463.
PubMed: 38943664
DOI: 10.1210/clinem/dgae443 -
Journal of Diabetes Investigation Jun 2024The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze...
AIM/INTRODUCTION
The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use.
MATERIALS AND METHODS
Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes).
RESULTS
We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring.
CONCLUSIONS
This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post-marketing surveillance of semaglutide to understand its potential risks.
PubMed: 38943656
DOI: 10.1111/jdi.14229 -
Expert Opinion on Drug Safety Jun 2024The aim of this study is to provide guidance for refining medication protocols, developing alternative strategies, and enhancing protection against herpesvirus...
Recommendations for the selection of nucleoside analogues as antihuman herpesvirus drugs: a real-world analysis of reported cases from the FDA adverse event reporting system.
OBJECTIVE
The aim of this study is to provide guidance for refining medication protocols, developing alternative strategies, and enhancing protection against herpesvirus infections in personalized clinical settings.
METHODS
Adverse drug events (ADEs) data for anti-herpesvirus from the first quarter of 2004 to the fourth quarter of 2022 were collected from the FDA Adverse Event Reporting System (FAERS). Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) methods for data mining.
RESULTS
A total of 18,591, 24206, 6,150, and 419 reports of ADEs associated with acyclovir (ACV), valacyclovir (VACV), ganciclovir (GCV), and famciclovir (FCV) were screened and extracted from the FAERS. In this study, the report summarized the high frequency and strong correlation of ADEs for the four drugs at the Preferred Term (PT) level. Additionally, the analysis also identified the relationship between ADEs and factors such as age, gender, and severity of outcome at the System Organ Class (SOC) level.
CONCLUSION
The safety reports for the four-nucleoside analogue anti-herpesvirus drugs are diverse and interconnected. Dosing for patients with herpesvirus infections should be tailored to their specific conditions and the potential risk of disease.
PubMed: 38943630
DOI: 10.1080/14740338.2024.2374919 -
Japanese Journal of Clinical Oncology Jun 2024The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of...
Association of the modified Glasgow prognostic score and prognostic nutritional index with duration of oral anamorelin administration in patients with cancer cachexia: a retrospective cohort study.
BACKGROUND
The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin.
METHODS
The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death.
RESULTS
The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin.
CONCLUSION
Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.
PubMed: 38943560
DOI: 10.1093/jjco/hyae086 -
Hepatology Research : the Official... Jun 2024Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell...
Cytokine release syndrome following durvalumab and tremelimumab in advanced hepatocellular carcinoma: A case report with cytokine and damage-associated molecular pattern analysis.
Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell hyperactivation caused by therapeutic agents, pathogens, cancers, and autoimmune diseases. In recent years, CRS has emerged as a rare, but significant, immune-related adverse event linked to immune checkpoint inhibitor therapy. Furthermore, several previous studies suggested that damage-associated molecular patterns (DAMPs) could be involved in malignancy-related CRS. In this study, we present a case of severe CRS following combination therapy with durvalumab and tremelimumab for advanced hepatocellular carcinoma, which recurred during treatment, as well as an analysis of cytokine and DAMPs trends. A 35-year-old woman diagnosed with hepatocellular carcinoma underwent a partial hepatectomy. Due to cancer recurrence, she started a combination of durvalumab and tremelimumab. Then, 29 days post-administration, she developed fever and headache, initially suspected as sepsis. Despite antibiotics, her condition worsened, leading to disseminated intravascular coagulation and hemophagocytic syndrome. The clinical course and elevated serum interleukin-6 levels led to a CRS diagnosis. Steroid pulse therapy was administered, resulting in temporary improvement. However, she relapsed with increased interleukin-6, prompting tocilizumab treatment. Her condition improved, and she was discharged on day 22. Measurements of inflammatory cytokines interferon-γ, tumor necrosis factor-α, and DAMPs, along with interleukin-6, using preserved serum samples, confirmed marked elevation at CRS onset. CRS can occur after the administration of any immune checkpoint inhibitor, with the most likely trigger being the release of DAMPs associated with tumor collapse.
PubMed: 38943555
DOI: 10.1111/hepr.14088 -
Journal of Gastroenterology and... Jun 2024We aimed to verify the effectiveness of electroacupuncture on postoperative ileus prevention after abdominal surgery by meta-analysis and trial sequential analysis (TSA). (Review)
Review
Effectiveness of electroacupuncture on postoperative ileus prevention after abdominal surgery: A systematic review and trial sequential analysis of randomized controlled trials.
BACKGROUND
We aimed to verify the effectiveness of electroacupuncture on postoperative ileus prevention after abdominal surgery by meta-analysis and trial sequential analysis (TSA).
METHODS
From inception to May 14, 2024, PubMed, the Cochrane Library, Web of Science, and Embase databases were searched. TSA was used to determine an optimal sample size and control false-positive findings. The primary outcome was the time to first defecation (hours).
RESULTS
Fourteen studies were included, with 1105 participants. Meta-analysis and TSA revealed firm evidence for benefits that electroacupuncture shorted the time to first defecation (mean difference [MD] -12.73 h, I = 22%, P < 0.01), the time to first flatus (MD -7.03 h, I = 25%, P < 0.01), the time to start of sips of water (MD -12.02 h, I = 0%, P < 0.01), and the time to start of liquid diet (MD -12.97 h, I = 0%, P < 0.01) compared with usual care. While compared with sham electroacupuncture, meta-analysis and TSA also confirmed that electroacupuncture shortened the time to first defecation (MD -10.81 h, I = 31%, P = 0.02) and the time to first flatus (MD -10.81 h, I = 0%, P < 0.01). However, TSA revealed that firm evidence for benefit or futility was not reached for the length of hospital stay and the rates of postoperative prolonged ileus.
CONCLUSIONS
Electroacupuncture shortened the duration of postoperative ileus in patients undergoing abdominal surgery, and the adverse events related to electroacupuncture were minor. Further investigation of the effect of electroacupuncture on the risk of prolonged postoperative ileus is warranted in the future.
PubMed: 38943533
DOI: 10.1111/jgh.16670 -
Otolaryngology--head and Neck Surgery :... Jun 2024This study aims to examine the adverse events associated with hypoglossal nerve stimulator (HNS) implantation for treating obstructive sleep apnea (OSA), drawing data...
OBJECTIVE
This study aims to examine the adverse events associated with hypoglossal nerve stimulator (HNS) implantation for treating obstructive sleep apnea (OSA), drawing data from the Manufacturer and User Facility Device Experience (MAUDE) database. We aim to provide a comprehensive and updated account of these adverse events.
STUDY DESIGN
Retrospective analysis.
SETTING
MAUDE Database review.
METHODS
A retrospective analysis was performed on the MAUDE database to collect all HNS-related reports from May 2014 to December 2023. Variables collected included date of event, event description, nature of event, iatrogenic injuries, required interventions, and, if available, root causes. Each event description was analyzed to classify the adverse event, the postevent intervention, and device model number.
RESULTS
Out of 1178 reports fulfilling the inclusion criteria, 1312 adverse events were identified. Common adverse events included infection (24.0%), pain (19.7%), and hematoma/seroma (10.2%). Approximately 83.1% of these adverse events necessitated medical and/or surgical intervention. The most frequent procedures included explantation (29.4%) and device repositioning (15.8%). Pneumothorax was reported in 50 cases, with 41 (82.0%) requiring a chest tube to be inserted. Three adverse events described overstimulation in the setting of magnetic resonance imaging (MRI) despite the implantation of MRI-compatible second-generation internal pulse generators.
CONCLUSION
While HNS implantation has been established as a reliable intervention for OSA in cases of continuous positive airway pressure failure or intolerance, this study highlights several perioperative and postoperative difficulties and complications. Understanding these challenges is essential for refining surgical practices and enhancing patient consent processes, ultimately aiming to improve therapeutic outcomes.
PubMed: 38943447
DOI: 10.1002/ohn.883 -
Autism Research : Official Journal of... Jun 2024This study aimed to document the safety and efficacy of a single infusion of autologous umbilical cord blood (UCB) in 20 autistic children aged 24-72 months. A...
Autologous umbilical cord blood infusion for the treatment of autism in young children: A within-subjects open label study on safety (assessed via caregiver report) and efficacy.
This study aimed to document the safety and efficacy of a single infusion of autologous umbilical cord blood (UCB) in 20 autistic children aged 24-72 months. A pre-post treatment within-subjects open label design was used. At T = 0, 6, 12, and 18 months, participants underwent detailed and structured safety evaluations (via caregiver report), Vineland Adaptive Behavior Scale (Vineland-3), Stanford Binet Intelligence Scale (SB-5), Expressive One-Word Picture Vocabulary Test, Brief Observation of Social Communication Change (BOSCC), Pervasive Developmental Disorder-Behavior Inventory, Repetitive Behavior Scale-Revised, Sensory Experience Questionnaire (SEQ-2.1), Child Behavior Checklist, Clinical Global Impression-Severity and Improvement (CGI-I) Scales, and eye-gaze tracking. UCB infusion was conducted at T = 6 months, hence, 0-6 months was the control period, and 6-18 months the follow-up period. Of 20 children recruited, 19 completed the study and 1 was withdrawn due to UCB not meeting quality control criteria for infusion. There were 15 males and 4 females with an overall mean (SD) age of 4.15 (0.62) years. Mean (SD) cell dose administered was 38.16 (9.82) million cells/kg. None suffered serious adverse events although there were mild behavioral side effects and one unit grew coagulase negative staphylococcus from a post-thaw sample. There were no significant differences in Vineland-3, SB-5, BOSCC, and SEQ-2.1 scores at T = 12 and T = 18 months. Twelve participants had T = 18 CGI-I scores of 2-3 (minimally to much improved), seven participants had scores of 4 (no change). Autologous UCB infusion in autistic children is generally safe but not without risks, including that of infection. In this within-subjects study, some children showed global symptom improvements while others showed no change. Stem cell therapies for autism should only be conducted under strict clinical trial conditions with clear risk discussions.
PubMed: 38943428
DOI: 10.1002/aur.3187 -
NeuroRehabilitation 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder diagnosed by motor symptoms of bradykinesia, in combination with tremor, rigidity, or postural... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder diagnosed by motor symptoms of bradykinesia, in combination with tremor, rigidity, or postural instability. Many studies document the effects of exercise-based interventions, but the benefit of different exercise types remains unclear.
OBJECTIVE
To provide a commentary on the Cochrane Review by Ernst et al. on the effectiveness of different types of physical exercise regarding motor signs, Quality of Life (QoL), and the occurrence of adverse events.
METHODS
A systematic search was performed in CENTRAL, MEDLINE, Embase, and other databases. The search was performed also in trial registries, conference proceedings, and reference list of identified studies.
RESULTS
The review included 154 RCTs (with 7837 participants). The network meta-analyses (NMAs) on the severity of motor signs and QoL included data from 60 (2721 participants) and 48 (3029 participants) trials, respectively. The evidence from the NMA suggests that dance, gait/balance/functional training probably have a moderate beneficial effect on the severity of motor signs, and multi-domain training probably has a small beneficial effect on the severity of motor signs. Endurance, aqua-based, strength/resistance, and mind-body training might have a small beneficial effect on the severity of motor signs. In addition, aqua-based training probably has a large beneficial effect on QoL, and mind-body, gait/balance/functional, and multi-domain training and dance might have a small beneficial effect on QoL.
CONCLUSIONS
Current evidence supports the promotion of physical exercise among people with PD, identifying only small differences between exercises in influencing the severity of motor signs and QoL.
Topics: Humans; Parkinson Disease; Quality of Life; Exercise Therapy
PubMed: 38943407
DOI: 10.3233/NRE-246004