Clinical Tolerability Research Articles

Commissioning of a commercial treatment planning system for scanned carbon-ion radiotherapy.

To commission the RayStation (RS) TPS (treatment planning system) for scanned CIRT (carbon-ion radiotherapy) utilizing pencil beam algorithms (PBv4.2). The beam model commissioning entailed employing 1D single beams and 2D monoenergetic fields to validate spot profiles with films, assess beam range using Peakfinder measurements, and evaluate fragment spectra through dose-averaged linear energy transfer (LETd) calculations. 3D dose distributions were verified in homogeneous phantoms for both absorbed and relative biological effectiveness (RBE)-weighted doses, and further assessed in double wedge and anthropomorphic phantoms for absorbed dose only. Finally, RBE-weighted dose verification and patient-specific quality assurance were conducted using 58 beams from 20 clinically treated patient plans. The results demonstrated good agreement in absolute dose distribution between TPS calculations and measurements, with mean dose discrepancies within 3%. However, deviations were slightly higher (>1%) for the cases involving the range shifter (RaShi) compared to those without the RaShi (<1%). Beam range, depth dose distribution, and lateral profiles of spread-out Bragg peaks (SOBPs) closely matched between RS TPS calculations and measurements. Some discrepancies (less than 0.5mm) were observed at field edges and in penumbra regions due to limitations in simulating asymmetrical spots, but within clinical tolerance. After model tuning, RBE-weighted dose calculations in RS TPS were in agreement with those from the clinically used TPS, except for variations exceeding 3% observed at energies exceeding 408.07 MeV/u, primarily attributed to fragment spectra differences. Overall, this study validated the RS TPS for calculating absorbed doses against measurements and RBE-weighted doses against a clinically used TPS. The results suggested that the RS TPS could be utilized for CIRT treatment planning, except for energies exceeding 408.07 MeV/u.

Opioid antagonists: clinical utility, pharmacology, safety, and tolerability.

Opioid antagonists block opioid receptors, a mechanism associated with utility in several therapeutic indications. Here, we review the sites of action, clinical uses, pharmacology, and general safety profiles of US Food and Drug Administration (FDA)-approved opioid antagonists. A review of the literature and product labels of opioid antagonists was conducted. The unique clinical uses of approved opioid antagonists are related to their ability to block opioid receptors centrally and/or peripherally. Centrally acting opioid antagonists treat opioid and alcohol use disorders (AUDs) and reverse opioid overdose. Because the opioid system influences weight and metabolism, one opioid antagonist combination product is approved for chronic weight management; another, approved for adults with schizophrenia or bipolar I disorder, mitigates olanzapine-associated weight gain. Peripherally acting opioid antagonists are approved for opioid-induced constipation; another accelerates gastrointestinal recovery after bowel surgery. Opioid antagonists are generally well tolerated; they are not associated with physiologic dependence or abuse. However, opioid antagonists can precipitate acute opioid withdrawal in patients using or undergoing withdrawal from opioid agonists. Likewise, their use can confer a risk for opioid overdose if attempts are made to overcome opioid antagonist blockade of opioid receptors via the intake of additional opioids. Opioid receptor antagonists have diverse therapeutic benefits based on their respective pharmacology and sites of action; understanding their respective nuances facilitates the safe and effective use of these agents.

Efficacy and Safety of Vuong Hoat Natural Health Supplement in Managing Low Back Pain: A Randomized Clinical Trial.

This clinical study aimed to assess the effectiveness and safety of Vuong Hoat (VH) natural health supplement for reducing the negative impact of low back pain, improving the quality of life, and enhancing functional activities in patients with lumbar degenerative disc disease (LDD). The open-label, randomized, controlled clinical trial involved 60 patients suffering from low back pain caused by LDD. The participants were randomly assigned to either a study group (SG) comprising 30 subjects or a control group (CG) comprising 30 subjects. Patients in the CG received treatment with electro-acupuncture, while those in the SG were administered VH in conjunction with the same electro-acupuncture protocol for 28 days. The clinical progression and tolerability of both groups were compared based on seven objective measurements: visual analog scale index, Schober test, fingertip-to-floor distance, spinal flexion, spinal extension, spinal tilt, and spinal rotation. After 14 days of treatment, the SG showed a significant improvement in overall outcomes compared to the CG. Specifically, 43.3% of SG patients achieved very good results, 53.3% had good results, and 3.4% had moderate results, whereas corresponding figures for the CG were 6.7%, 76.7%, and 16.6%, respectively (P < .05). After 28 days of treatment, both groups demonstrated a shift toward very good results, with the SG continuing to show better outcomes than the CG (P < .05). In the SG, the very good results increased to 76.7%, good results decreased to 20%, and moderate results were 3.3%. On the other hand, the CG had 46.7% very good results, 43.3% good results, and 10% moderate results. Notably, no side effects were reported from the VH treatments during the study. The findings of this study indicate that VH health supplement is a safe and effective approach for managing low back pain and limited spinal movement in patients with LDD.

Accuracy of an Activity Monitor in Assessing Physical Activity of Hospitalized Geriatric Rehabilitation Patients With Slow Walking Speed Using a Walking Aid.

Accurate assessment of physical activity is essential in hospital settings, but difficult for geriatric rehabilitation patients who have slow walking speed and rely on walking aids. This study conducted an external validation of the MOX activity monitor accuracy in distinguishing between sedentary (lying, sitting), standing, and dynamic activities among hospitalized geriatric rehabilitation patients. Additionally, the study assessed clinical tolerance and ease of use of the monitor. Inclusion criteria were being hospitalized on the geriatric rehabilitation ward, aged 70years or older, and using a walking aid. The monitor was placed on the upper leg, and remained in place for 1 week. In a test-session, four activities of 4min each (lying, sitting, standing, and walking) were filmed. Video analyses created a direct observation timeline. Daily skin irritation assessments were conducted and participants noted their discomfort level at the week's end. The study included 20 participants who relied on walking aids, with 10 requiring additional physical support while walking. The MOX activity monitor exhibited excellent accuracy in classifying the four activities, with a zero mean percentage error for sedentary activity, 2.2% for standing, and 2.7% for walking. Participants reported minimal hindrance, and the monitor proved user-friendly. The MOX activity monitor demonstrated remarkable accuracy in distinguishing between these four activities in a test-session and displayed strong clinical applicability. The monitor shows substantial promise as a valuable tool for assessing physical activity in hospitalized geriatric rehabilitation patients using walking aids.

Allergen Immunotherapy: Optimal Duration for Respiratory Allergy

Abstract Purpose of the Review To analyse the evidence regarding the optimal duration of subcutaneous and sublingual immunotherapies to induce long-lasting benefits after treatment cessation for allergic rhinitis and asthma and to identify unmet needs. Recent Findings Subcutaneous and sublingual immunotherapies are highly effective in desensitising selected subjects with allergic rhinitis and allergic asthma. Double-blind, placebo-controlled, randomised clinical trials of both routes of immunotherapy support international guidelines that recommend their use for at least three years to achieve disease modification and continued clinical and immunological tolerance for allergic rhinitis. Evidence of the long-term effects of allergen immunotherapy in the context of randomised controlled trials for allergic asthma as opposed to rhinitis is limited. Nonetheless, real-world studies suggest the long-lasting benefits of allergen immunotherapy for allergic asthma, as this reduces prescriptions for pharmacotherapy and decreases the risk of asthma exacerbations and hospitalisations. The GINA guideline 2023 recommends the use of house dust mite sublingual immunotherapy as an add-on therapy in subjects with suboptimally controlled asthma, despite the use of low to high doses of inhaled corticosteroids, provided that the FEV1 is &gt; 70% predicted. Summary Robust clinical trials of subcutaneous and sublingual immunotherapies have shown that 3 years of continuous treatment modifies the underlying course of allergic rhinitis with long-lasting clinical effects years after withdrawal. Further evaluations of the long-lasting effects of novel routes of allergen immunotherapy for allergic rhinitis and long-term studies for allergic asthma are needed in the context of randomised clinical trials.

Unveiling tyrosinase inhibitors: current challenges and future directions in hyperpigmentation therapy

An ideal topical depigmenting agent acts quickly, and it selectively targets the melanocytes with appreciable clinical efficacy and tolerability. Traditionally, tyrosinase inhibitors (Tyri) such as kojic acid, hydroquinone and arbutin have been used both as treatment agents and reference molecules for evaluating new depigmenting agents. Amongst thousands of depigmenting molecules, only few have been successfully incorporated into topical depigmenting formulations but that too with limited clinical efficacy. To understand the paradox between in vivo and in vitro efficacy of available agents, this article focusses on the testing systems for depigmenting molecules, accepted mechanism of actions, and their lesser-known effects contributing to efficacy/side effects.

Dexamethasone improves clinical and biological tolerance of transcatheter arterial chemoembolization for hepatocellular carcinoma

BackgroundTransarterial chemoembolization (TACE) is widely used for hepatocellular carcinoma treatment but side effects hamper tolerance. Dexamethasone reduces TACE side effects in patients with viral hepatitis, but data regarding alcohol and metabolic liver diseases are lacking. We aimed to evaluate the efficacy of dexamethasone in preventing TACE-associated adverse events in European populations with predominantly alcoholic and metabolic cirrhosis. MethodsAll cirrhotic patients undergoing TACE in our center between 2017 and 2021 were included. Dexamethasone was added to our protocol from 2019. Using a quasi-experimental study design, patients before and after introduction of dexamethasone in our procedure were compared. Factors associated with TACE adverse events were assessed by univariate and multivariate analysis. A sensitivity analysis was performed using propensity scores for covariate adjustment. Results234 patients undergoing 398 TACE procedure were included. Cirrhosis was predominantly of alcohol or metabolic etiology (86.7 %). Dexamethasone was administered in 99 procedures (24.9 %). Incidence of fever and encephalopathy at day 2 after TACE was lower in the Dexamethasone group (p < 0.001; p = 0.02 respectively). In multivariate analysis, dexamethasone was associated with lower occurrence of fever (OR=0.03; p < 0.001), lower analgesics use (OR=0.11; p = 0.002), milder liver and kidney function impairment (OR=0.98; p = 0.001 and OR=0.94; p < 0.001 for bilirubin and creatinine variation respectively). Propensity score-adjusted analyses yielded similar results. ConclusionDexamethasone improves TACE tolerance in a population of predominantly metabolic and alcohol cirrhosis.

Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors.

Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting 90Y- and 177Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with 213Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated 213Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16-77 y were treated with a mean of 1,609 MBq of 213Bi-FAPI-46, fractionated into 53 single applications (range, 5-12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. 18F-FDG (4 patients) and 68Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with 213Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and -24.3%, respectively), slightly decreased in the patient with stable disease (-10.6% and -5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter 213Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the 177Lu- or 90Y-labeled compounds. In this pilot project, fractionated RPT with 213Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT.

Observational Study with a New Portable Cryosurgery Device, HYDROZID®, in Superficial Epidermal Lesions: An Indian Experience

Abstract Background: Cryosurgery remains an important treatment modality in dermatology practice. HYDROZID®, a new portable cryosurgery medical device using norflurane as a cryogen, was recently introduced in the Indian market. This paper reports the findings of the phase IV study conducted in India. Aims: This is a prospective phase IV study to evaluate its safety and efficacy in the treatment of superficial epidermal and dermal lesions. Methods: The study was conducted across 4 centres in India. The cryosurgery cycles were decided based on the skin lesion considered for the treatment. Safety and efficacy parameters were assessed at day 1, day 7, day 14, day 30 (±2) (end of treatment), and day 60 (±2) after the initial cryosurgery treatment. The local skin reactions scale, pain VAS scale, and Vancouver scale for assessment of pigmentation and scarring were used for the assessment of cutaneous reactions. Assessment of efficacy was done by evaluating the total disappearance of skin lesions at the end of the study visit. Results: Ninety-seven patients completed the study. The reported post-procedural pain was mild to moderate and subsided over the period of 24 hours. There was no pain observed in 84.76% of patients at the end of 24 hours. Complete disappearance of the lesion was seen in 47.4% of patients at the end of the study, while the reduction in the diameter of skin lesions by more than 50% was observed in 79.38% of patients. Conclusion: The data from this study support good clinical tolerability and safety of the Hydrozid® portable cryo device.

Clinical Efficacy and Tolerability of Lemon Balm (Melissa officinalis L.) in Psychological Well-Being: A Review

Background: There is renewed interest in the use of ancient herbal remedies for their potential health benefits, particularly in the psychological domain. One herb that is receiving growing attention is lemon balm (Melissa officinalis L.) which has received considerable interest for its influence on the brain. Lemon balm boasts an array of phytochemicals, including rosmarinic acid, citral, oleanolic acid, and ursolic acid, which are believed to underpin these effects on psychological well-being. Pharmacological evidence from animal and cellular work reveals that lemon balm and its components may modulate several brain signalling pathways, including GABAergic, cholinergic, and serotonergic systems. Results/Conclusions: Although further robust randomised controlled trials using lemon balm are required, existing research indicates that lemon balm holds promise as a calming agent exhibiting both anxiolytic and anti-depressant properties and can elicit cognitive and sleep-quality enhancement.

Evaluating CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: A Retrospective Real-World Multicenter Study

Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events.

The Clinical Effectiveness and Tolerability of Oseltamivir in Unvaccinated Pediatric Influenza Patients during Two Influenza Seasons after the COVID-19 Pandemic: The Impact of Comorbidities on Hospitalization for Influenza in Children.

Antiviral therapy such as oseltamivir has been recommended for hospitalized children with suspected and confirmed influenza for almost 20 years. The therapy is officially authorized for newborns two weeks of age or older, however, questions about its safety and effectiveness still surround it. Our goals were to assess the epidemiological features of two consecutive seasonal influenza cases in children following the COVID-19 pandemic; to observe the clinical effectiveness and tolerability of oseltamivir in hospitalized children who were not vaccinated against influenza and had different influenza subtypes, including A(H1N1), A(H3N2), and B; and to identify specific comorbidities associated with influenza in children. We performed an observational study on 1300 children, enrolled between 1 October 2022 and 30 May 2023 and between 1 October 2023 and 4 May 2024, to the IX Pediatric Infectious Diseases Clinical Section of the National Institute of Infectious Diseases "Prof. Dr. Matei Balș". During the 2022-2023 influenza season, 791 pediatric patients tested positive for influenza and received oseltamivir. Of these, 89% (704/791) had influenza A, with 86.4% having subtype A(H1N1) and 13.6% of cases having A(H3N2), and for influenza B, 11% (87/791) of the pediatric patients. Of the total group, 59% were male, and the median age was 2.4 years (1.02-9.28). For the 2023-2024 influenza season, 509 pediatric patients tested positive for influenza, with 56.9% being of the male gender and who were treated with oseltamivir. Of these patients, 81.6% had influenza A and 18.4% had influenza B. Treatment with neuraminidase inhibitors, specifically oseltamivir, 2 mg/kg/dose administered twice daily for 5 days, was well tolerated by the children, and we recorded no deaths. The duration of hospitalization for patients with a fever after the oseltamivir administration was significantly longer for patients with A(H1N1) infection than A(H3N2), during both seasons. We identified more complications in the 2022-2023 season and a decreasing number of influenza B for the 2023-2024 season. Among children with comorbidities, the most common were asthma, gastrointestinal diseases, and metabolic and endocrine diseases. In terms of effectiveness, oseltamivir significantly reduced the intensity of influenza symptoms, thus reducing the number of days of hospitalization (p = 0.001) as well as post-infection complications (p = 0.005) in both groups. In this study, we evaluated the clinical effectiveness of oseltamivir therapy for all influenza types/subtypes in children, and the length of hospitalization. We identified comorbidities associated with the prolonged duration of hospitalization. Influenza vaccination should be the main tool in the prevention of influenza and its complications in children, especially those with comorbidities.

Long-term performance monitoring of a-Si 1200 electronic portal imaging device for dosimetric applications.

Recently, dosimetri applications of the electronic portal imaging device (EPID) in radiotherapy have gained popularity. Confidence in the robust and reliable dosimetric performance of EPID detectors is essential for their clinical use. This study aimed to evaluate the dosimetric performance of the a-Si 1200 EPID and assess the long-term stability of its response. Weekly measurements were performed on two clinically used TrueBeam linear accelerators (linacs) equipped with a-Si 1200 EPID detectors over a 2-year period. They included dark and flood calibration fields, and EPID response to an open field corrected for the long-term machine output drift measured with the secondary absolute dosimeters: an ion chamber and an ion chamber array. All measurements were performed using five photon beam energies and two imaging modes: continuous and dosimetry. The measurements were analyzed for constancy and the presence of long-term trends. Comparisons were made between the two linacs for each beam energy. Pixel sensitivity matrices (PSM) were determined semi-annually and analyzed for long-term constancy for both treatment machines. The long-term variation of the dark and flood field signals, integrated across the EPID plane, over the entire observation period did not exceed 0.17% and 0.79%, respectively. The output-corrected EPID response showed long-term variation from 0.28% to 0.36%, depending on beam energy, while the short-term variation was 0.04%-0.07% for EPID and 0.02%-0.06% for secondary dosimeters. The long-term variation of secondary dosimeters was 0.2%-0.3%. PSMs were found to be stable to within 1% for 97.8% of pixels and 2% for 100% of pixels. Techniques to monitor and assess the long-term performance of the a-Si 1200 EPID as a dosimeter were developed and implemented using two TrueBeam linacs. The long-term variation of the EPID response was within clinical tolerance indicated in AAPM TG-142 report, and the detector was shown to be stable and reproducible for routine clinical dosimetry.

Efficacy of perampanel by etiology in Japanese patients with epilepsy-subpopulation analysis of a prospective post-marketing observational study.

To examine the efficacy and safety of perampanel (PER) in patients with post-stroke epilepsy (PSE), brain tumor-related epilepsy (BTRE), and post-traumatic epilepsy (PTE) using Japanese real-world data. The prospective post-marketing observational study included patients with focal seizures with or without focal to bilateral tonic-clonic seizures who received PER combination therapy. The observation period was 24 or 52 weeks after the initial PER administration. The safety and efficacy analysis included 3716 and 3272 patients, respectively. This post hoc analysis examined responder rate (50% reduction in seizure frequency), seizure-free rate (proportion of patients who achieved seizure-free), and safety in patients included in the post-marketing study who had PSE, BTRE, and PTE in the 4 weeks prior to the last observation. Overall, 402, 272, and 186 patients were included in the PSE, BTRE, and PTE subpopulations, and 2867 controls in the "Other" population (etiologies other than PSE, BTRE, or PTE). Mean modal dose (the most frequently administered dose) values at 52 weeks were 3.38, 3.36, 3.64, and 4.04 mg/day for PSE, BTRE, PTE, and "Other," respectively; PER retention rates were 56.2%, 54.0%, 52.6%, and 59.7%, respectively. Responder rates (% [95% confidence interval]) were 82% (76.3%-86.5%), 78% (70.8%-83.7%), 67% (56.8%-75.6%), and 50% (47.9%-52.7%) for PSE, BTRE, PTE, and "Other," respectively, and seizure-free rates were 71% (64.5%-76.5%), 62% (54.1%-69.0%), 50% (40.6%-60.4%), and 28% (25.8%-30.1%), respectively. Adverse drug reactions tended to occur less frequently in the PSE (14.7%), BTRE (16.5%), and PTE (16.7%) subpopulations than in the "Other" population (26.3%). In real-world clinical conditions, efficacy and tolerability for PER combination therapy were observed at low PER doses for the PSE, BTRE, and PTE subpopulations. To find out how well the medication perampanel works and whether it is safe for people who have epilepsy after having had a stroke, brain tumor, or head injury, we used information from real-life medical situations in Japan. We looked at the data of about 3700 Japanese patients with epilepsy who were treated with perampanel. We found that perampanel was used at lower doses and better at controlling seizures, and had fewer side effects for patients with epilepsy caused by these etiologies than the control group.

Clinical utility of ultra long-term subcutaneous electroencephalographic monitoring in drug-resistant epilepsies: a "real world" pilot study.

This study was undertaken to assess the clinical utility, safety, and tolerability in epilepsy patients of ultra long-term monitoring with a novel subcutaneous electroencephalographic (EEG) device (sqEEG). Five patients with drug-resistant focal epilepsy were implanted (one patient bilaterally) with sqEEG. In phase 1, we assessed sqEEG sensitivity for seizure recording by recording seizures simultaneously with scalp EEG in the epilepsy monitoring unit (EMU). sqEEG was scored either visually (v-sqEEG) or by using a semiautomatic algorithm (EpiSight; E-sqEEG). In phase 2, the patients were monitored as outpatients for 3-6 months. sqEEG data were analyzed monthly, evaluating concordance of data obtained by v-sqEEG, E-sqEEG, and patients' diaries. v-sqEEG data were used to guide treatment adjustments. sqEEG-related side effects were assessed throughout the study. In phase 1, v-sqEEG detected all seizures recorded in the EMU in all patients, whereas E-sqEEG was as effective in three patients. In the other two patients, E-sqEEG detected only a proportion or none of the seizures, respectively. Sensitivity of E-sqEEG depended on the ictal EEG features. In phase 2, a 100% concordance between E-sqEEG and v-sqEEG in seizure detection was observed for the same three patients as in phase 1. In the other two patients (one implanted bilaterally), effectiveness of E-sqEEG in detecting seizure as compared to v-sqEEG ranged from 0% to 83%. v-sqEEG showed that all patients reported in their diaries fewer seizures than they actually suffered. In four of five patients, v-sqEEG showed that the treatment adjustments had been ineffective or associated with a seizure increment. The only side effect was an infection at the implantation site in one patient. The sqEEG system could collect reliable information on seizure activity, thus providing clinically relevant information. Sensitivity of EpiSight in detecting seizures varied across patients, depending on the ictal EEG features. sqEEG ultra long-term monitoring was feasible and well tolerated.

Evaluation of the effect of cannabidiol administration with and without nonsteroidal anti-inflammatory drugs in dogs with mobility disorders: a prospective, double-blind, crossover, placebo-controlled study.

With rapidly growing interest in the use of cannabidiol (CBD) in the management of pain and other conditions, more information is needed on the safety and efficacy of this supplement, particularly its co-administration with commonly used pharmaceuticals such as non-steroidal anti-inflammatory drugs (NSAIDs). This study sought to assess the effect of CBD in dogs with mobility impairments, as well as evaluate the clinical tolerance of CBD used together with NSAIDs. Forty-two client-owned dogs with diagnosed mobility impairments were enrolled in this prospective, double-blind, crossover, placebo-controlled study. Baseline data were collected for 10-14 days followed by random allocation to either placebo or CBD oil for 45 days with a 30-day washout period in between. CBD was dosed at 5 mg/kg orally every 12 h with masked placebo administered at equal volume. Outcome measures included objective gait analysis, accelerometry, and clinical metrology instruments. CBD plasma levels and serum biochemistry were also collected along with hepatic ultrasound if warranted. Thirty-eight dogs finished the study with thirty-nine included for at least partial analysis. Compared to baseline, dogs receiving CBD showed evidence of improved outcomes based on blinded veterinary assessments and accelerometer data. Compared to placebo, dogs receiving CBD showed some evidence of improved outcomes on CBPI, CSOM, and blinded veterinary assessments, but not for objective outcome measures. There was evidence of increased ALP when CBD was co-administered with NSAIDs compared to CBD administration alone. Additionally, there was evidence of ALT elevations with CBD and NSAID co-administration, but this elevation did not show evidence of an increase over CBD use alone. These results suggest a potential therapeutic benefit in the administration of CBD for the management of mobility impairments, but greater ALP elevations were seen when administered with NSAIDs. While the sample size of dogs that received further hepatic work-up for liver enzyme elevations is small, chosen diagnostics varied, and liver biopsies were not performed, there did not appear to be clinically apparent liver damage. Further research is needed to better understand the efficacy of CBD in a larger population of dogs and patient tolerance and safety when administered with NSAIDs or other medications long term.

Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication.Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively.Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development.

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 .

Elexacaftor/tezacaftor/ivacaftor, a game-changer in cystic fibrosis: The Portuguese experience

BackgroundPhase 3 trials of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) combination treatment in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele showed profound short-term effects on lung function, weight, and pulmonary exacerbations (PEx). The authors conducted a 12-month study to add evidence on the real-world long-term effectiveness and safety of CFTR modulator therapy with ELX/TEZ/IVA in Portuguese CF adult population. MethodsAmbispective, multicentre, observational, real-life study involving all the Portuguese CF Reference Centres. Adult patients on treatment with ELX/TEZ/IVA combination outside clinical trials were included. Demographics, efficacy, and safety variables on the first 12 months of treatment were compared with the pre-treatment year. Results132 adult people with CF were included, of which 119 completed 12 months treatment (mean duration of treatment 21.5 months). Mean age was 31.7 ± 11.0 years, 53 % patients were homozygous for the F508del variant, baseline sweat chloride was 86.7 ± 25.9 mmol/L and pre-treatment percent-predicted FEV1 was 77.9 ± 19.7 %. At 1 year, mean absolute change from baseline in FEV1 was +0.46L (95 % CI: 0.37, 0.55; p < 0.001) and +13.9 percentage points (95 % CI: 11.5, 16.2; p < 0.001). PEx episodes decreased by 78 % (p < 0.001) and hospitalizations for PEx decreased by 91.4 % (p < 0.001). Body mass index (BMI) increased 1.2 kg/m2 (95 % CI: 0.9, 1.5; p < 0.001). Mean sweat chloride variation was −44.5 mmol/L (95 % CI: −49.8, −39.2; p < 0.001). No correlation was found between sweat chloride and lung function (r = −0.116, p = 0.335). There were no major safety concerns. Of note, headache was reported in 7.6 % and neuropsychiatric manifestations occurred in 12.6 % treated patients, being anxiety and depressive disorders the most common. ConclusionsELX/TEZ/IVA treatment in Portuguese adults with CF was associated with significant improvement in lung function, a drop in PEx and PEx-related hospitalizations and increase in BMI at 12 months and was well tolerated. These results add knowledge to our understanding of clinical benefits and tolerability of ELX/TEZ/IVA. Careful evaluation of adverse effects of ELX/TEZ/IVA therapy and its determinants, mainly concerning mental health, are a research priority.

Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results.

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting. We conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials. Between 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23-28). During a median follow-up of 9 months IQR (7-24), 27 patients discontinued cabotegravir/rilpivirine: 5 because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI. Data from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations.