Safety Evaluation Research Articles

Risk Identification and Safety Evaluation of Offshore Wind Power Submarine Cable Construction

To mitigate accidents in submarine cable construction within the rapidly expanding offshore wind power sector, this study employed the analytic hierarchy process (AHP) and risk matrix method (LS) to assess the risks associated with identified factors. Based on project research and expert consultations, five primary and twenty-two secondary risk factors were identified. AHP was utilized to rank the primary risk factors by severity, probability, and detection difficulty, with the highest risk being the environmental impact, followed by third-party destruction and worker error. LS was applied to rank the secondary risk factors by likelihood and severity, with the highest risks being complex submarine topography, low underwater visibility, and fishing operations. The study proposes risk reduction measures based on these evaluations and offers methodological guidance for improving construction safety in similar enterprises.

Assessing evacuation risks in prominent historical mosques: An integrated quantitative and qualitative approach via the HM-ERI framework

Historical mosques, with their unique architectural features and high occupant densities, pose distinct challenges for safe and efficient evacuation. This study introduces the Historical Mosque Evacuation Risk Index (HM-ERI), a novel and comprehensive framework specifically designed to assess evacuation risks in these culturally significant structures. The HM-ERI model integrates three quantitative criteria derived from agent-based simulations and seventeen qualitative criteria assessed through on-site evaluations, generating two dimensionless risk scores: HM-ERIQN (quantitative risk) and HM-ERIQL (qualitative risk). Analysisof 12 prominent 15th and 16th century mosques in Turkey revealed a spectrum of evacuation risk levels. The mosques' HM-ERIQN values ranged from 0.27 (low risk) to 0.80 (high risk) in the range of 0–1, indicating variations in potential congestion and evacuation efficiency based on simulated total evacuation times ranging from 2 min 46.3 s to 8 min 18.5 s. HM-ERIQL values, reflecting the severity of qualitative factors on a 0–1 scale such as the lack of alternative exits, improper placement of shoe racks, complex building layouts, and limited emergency preparedness, fell between 0.46 and 0.73, indicating moderate to high risks.By integrating expert judgment and utilizing data from both simulations and on-site observations, the HM-ERI framework provides a practical tool for identifying high-risk historical mosques and informing targeted interventions to enhance evacuation safety. This research contributes to developing enhanced evacuation standards for these culturally significant structures, enabling improved safety evaluations and guiding effective preservation strategies that prioritize human life and cultural heritage.

Coupling Dynamics Study on Multi-Body Separation Process of Underwater Vehicles

Based on the Newton-Euler method, a coupling rigid-body dynamics model of a Trans-Medium Vehicle (TMV) separating from an Unmanned Underwater Vehicle (UUV) has been established. The modeling is based on the “holistic method” and “Kane” ideas respectively, so that most of the equations can be derived without considering the internal forces between the two bodies. The separation propulsion force, which is an internal force, only appears in the relative glide dynamics equation of the TMV along the axis of the separation tube that is installed on the UUV. This greatly reduces the workload of modeling and derivation. The UUV works entirely underwater, while the hydrodynamic shape of the TMV changes continuously during the process of the TMV separating from the UUV. Therefore, accurate hydrodynamic calculations for the UUV and TMV are the basis of numerical resolution for the two rigid bodies’ coupling dynamics model in water. A large number of numerical simulations was conducted using CFD methods to investigate the hydrodynamic performance of the UUV and TMV under various conditions. These simulations aim to establish a hydrodynamic database, and accurate hydrodynamic models were developed through fitting methods and online interpolation. In the process of solving the coupling dynamics of two bodies, the hydrodynamic model is used to calculate the hydrodynamic force experienced by the UUV and TMV. This balances the accuracy and efficiency of a numerical simulation. Finally, numerous simulations and comparative analyses were conducted under various operational conditions and separation parameters. The simulation results indicate that the impact of TMV separation on the motion state of the UUV becomes more prominent with smaller UUV to TMV mass ratios or deeper TMV separation depths. This effect can further influence the stability control of the UUV. The coupling rigid body dynamics analysis method established in this paper provides a fast and effective prediction method for use during the scheme design and separation safety evaluation phases of creating UUV-TMV systems.

Safety Evaluation of Carbon Dots in UM-UC-5 and A549 Cells for Biomedical Applications

Backgroung: The rising complexity and associated side effects of cancer treatments highlight the need for safer and more effective therapeutic agents. Carbon-based nanomaterials such as CDs have been gaining prominence for their unique characteristics, opening avenues for diverse applications such as fluorescence imaging, drug and gene transport, controlled drug delivery, medical diagnosis, and biosensing. Despite promising advancements in research, it remains imperative to scrutinize the properties and potential cytotoxicity of newly developed CDs, ensuring their viability for these applications. Methods: We synthesized four N-doped CDs through a hydrothermal method. Cell viability assays were conducted on A549 and UM-UC-5 cancer cells at a range of concentrations and incubation times, both individually and with the chemotherapeutic agent 5-fluorouracil (5-FU). Results: The obtained results suggest that the newly developed CDs exhibit suitability for applications such as bioimaging, as no significant impact on cell viability was observed for CDs alone.

Pilot Clinical Safety and Efficacy Evaluation of a Topical 3% Tranexamic Acid Cream and Serum Protocol for Managing Facial Hyperpigmentation in Caucasian Patients

Facial hyperpigmentation is a highly prevalent dermatological condition, characterized by dark spots on the skin resulting from excess melanin production. Hyperpigmentation significantly impacts patients’ quality of life and self-esteem. Current treatments often present disadvantages linked to poor product tolerability. A topical cosmetic approach combining three lightening active ingredients (tranexamic acid, niacinamide, vitamin C) offers a new option for treating dark spots on the skin. The present in-use test under dermatological control evaluated the clinical safety and efficacy of a cream and serum containing these three ingredients, formulated with hyaluronic acid for enhanced delivery, stability, and efficacy. A total of 22 Caucasian patients with facial hyperpigmentation, both male and female, aged between 45 and 67 years, applied the cream and serum for 8 weeks. Clinical assessments, colorimetric evaluations, standardized photography, and self-assessment questionnaires were used to measure outcomes. No serious adverse effects were recorded, and the incidence of local adverse effects was low, highlighting good tolerability of the investigated test items. In most participants, significant improvements in hyperpigmented areas were recorded. Clinical scoring by the dermatologist investigator indicated a statistically significant 13% reduction in color intensity and a 6% reduction in the size of dark spots after 8 weeks of treatment. Colorimetric evaluation showed a statistically significant 1% increase in luminosity (L* parameter) and an 8% improvement in the Individual Typological Angle (ITA°) in endpoint, indicating lighter skin spots. Subjective assessments reflected high user satisfaction, with 95% of participants noting improvements in skin hydration and luminosity, and 77% reporting a reduced appearance of dark spots. Overall, the present work supports the use of tranexamic acid, niacinamide, and vitamin C as an effective and well-tolerated combined topical management option for hyperpigmentation. This combination offers a viable alternative to classical whiteners for individuals seeking to reduce facial skin coloration imbalance and improve skin tone.

Safety Evaluation and antioxidant potential of new probiotic strain Bacillus subtilis (NMCC-path-14) in Balb/c mice by sub-acute repeated dose toxicity

Probiotics have recently gained significant interest for their possible therapeutic effects in treating numerous health conditions. Probiotics containing Bacillus subtilis have been shown to have several health benefits, most notably in preventing diarrhea and gastrointestinal problems. A novel probiotic strain, Bacillus subtilis (NMCC-path-14), isolated from the rumen of a Nilli Ravi Buffalo, was evaluated for 28-day repeated dose toxicity in Balb/c mice. The NMCC-path-14 in low dose (1 × 108 CFU/ml) and high dose (1 × 1010 CFU/ml) was administered to the mice through gavage regularly. After 28 days of treatment, it was discovered that the no-observed-adverse-effect level (NOAEL) for NMCC-path-14 wasgreater than 1 × 1010 CFU/animal/day. This study also revealed no treatment-related changes in clinical parameters, body weight, gross pathology, or histology. Food consumption, hemoglobin, hematocrit, red blood cell counts, and colon length increased, while total/differential leukocyte count and platelets remained unchanged. The administration of NMCC-path-14 also resulted in decreased bilirubin and creatinine levels. Furthermore, NMCC-path-14 also displayed a promising antioxidant potential by increasing the antioxidant enzymes (GST, GSH, and CAT) and decreasing oxidant enzyme (MDA and NO) levels in vital organs like the liver, kidneys, spleen, and colon. TheNMCC-path-14also decreased the pathogenic bacterial population while increasing the beneficial population. Given the lack of adverse effects observed after NMCC-path-14 treatment, this strain is safe and must be considered as a potential probiotic in humans.

Ultrasound-Guided Percutaneous Tracheostomy in Cardiovascular and Thoracic Surgery of South Korea: Retrospective Evaluation of Efficacy and Safety in Critically Ill Patients.

In intensive care settings, the maintenance of ventilation is typically essential. Tracheostomy is frequently performed to facilitate long-term ventilation and to minimize associated complications. This procedure can be conducted using several techniques, including traditional surgery, endoscopic approaches, and ultrasound-guided methods. We retrospectively examined data from all patients admitted to the intensive care unit of our institution who underwent ultrasound-guided percutaneous tracheostomy (UPCT) between March 2018 and April 2023. The study included a total of 81 patients aged 15 years or older. To assess the incidence of complications, we classified these issues as either minor or major, with major complications encompassing events such as bleeding necessitating blood transfusion. The most frequent minor complication was bleeding that did not require blood transfusion, which occurred in 15 patients (18.5%). Major complications were identified in 7 patients (8.6%), all of whom experienced bleeding that necessitated transfusion. However, we noted no cases of infection, conversion to open surgery, or tracheal stenosis surgery. The complication rate did not significantly differ from those reported in previous studies. These results indicate that UPCT can be safely used in critically ill patients, although further research on this topic is needed.

Drug-Induced Mitochondrial Disruption in the Blood-Brain Barrier Cells: Overlooked Player in Drug Safety Evaluation.

The blood-brain barrier (BBB) is based on the unique pattern of the microvasculature of the central nervous system (CNS), which controls the transport of molecules between the CNS and the blood. The blood-brain barrier is mainly composed of endothelial cells, pericytes, and basement membrane, as well as the astrocytes and immune cells as perivascular macrophages and microglial cells. The dysfunction of this barrier can cause serious neuronal disorders due to the transport of hazardous molecules and immune cells to the CNS. Mitochondria plays a major role in cellular homeostasis in terms of health and disease. This review evaluated the published data about the effect of the drugs on the cells of BBB. Only seven articles were found that considered the effect of drugs on the barrier endothelial cells and mitochondria via different assays. Further studies are recommended to evaluate the impact of used medications on BBB cell bioenergetics. Also, the effect of the newly studied pharmaceutical agents on the BBB bioenergetics should be included within their safety profile studies.

Structural design and experimental verification of a thin-walled plastic chairs based on the finite element method

This study focuses on the design and preparation of a thin-walled plastic chair, and its mechanical properties were investigated by high load, cyclic load and drop impact. The finite element method (FEM) was employed to accurately evaluate the chair’s safety under these forces. Additionally, the effects of important structural parameters on the loading process in different states were investigated. Furthermore, a solid plastic chair prototype was created for experimental analysis. The findings revealed that increasing the thickness of the key structural parameters enhanced the safety properties of the chair under various load conditions. Optimal results were obtained when both dimensions were set to 5 mm. The deformation errors in FEM, experimental strength analysis, fatigue analysis, and drop impact analysis were measured at 3.7%, 3.6%, and 11.7%, respectively. Similarly, the stress errors were determined to be 5.9%, 5.2%, and 6.5%. These results suggest that the structural design of the chair demonstrates excellent reliability. Studying the crucial structural parameters of a plastic chair can provide valuable insights for the scientific design and safety evaluation of thin-walled furniture.

An in vitro study of a combined patient-specific device for safe and accurate insertion of infrazygomatic crest miniscrews.

To develop and assess the efficacy of a novel combined patient-specific device (CPSD) for the accurate and safe insertion of infrazygomatic crest miniscrews in orthodontic procedures. Twenty-eight miniscrews were placed in the infrazygomatic crest region of 28 cadaver maxillae using the direct manual method (n = 14) or the CPSD (n = 14) based on preset trajectories. The CPSD, designed based on the integration model, included a positioning guide, an insertion guide, and a depth-limiting groove. Deviations in the insertion site, tip location, insertion angle, and biting depth between the preset and real insertion trajectories were calculated to evaluate the accuracy of miniscrew insertion. Classification frequencies of root proximity, sinus penetration depth, and biting depth of the miniscrew after insertion were also calculated to evaluate the safety of miniscrew insertion. Regarding evaluation of accuracy, significant differences were observed in the deviation values of the insertion site, tip location, insertion angle, and biting depth between the CPSD and freehand groups (P = .001, P < .001, P < .001, P = .039, respectively). Regarding evaluation of safety, a significant difference was observed in the classification frequencies of root proximity between the two groups (P = .016). Compared with manual insertion, CPSD could be a preferred method for safe and accurate insertion of infrazygomatic crest miniscrews for orthodontists.

High volume nasal irrigations with steroids for chronic rhinosinusitis and allergic rhinitis.

The primary aim of this systematic review is to assess the efficacy, safety, and cost-effectiveness of high-volume steroid nasal irrigation (SNI) for treating chronic rhinosinusitis (CRS) and allergic rhinitis (AR). A systematic review of literature from 2012 to 2024 was conducted using PubMed to identify relevant studies. The search focused on terms related to AR, CRS, and steroid nasal irrigation. Studies were screened for relevance and duplicates removed, resulting in 20 studies being included in the final analysis. These studies were categorized based on their focus on efficacy, safety, or both, and underwent a risk of bias assessment using Cochrane and ROBINS-I tools. Of the 20 studies included, 13 examined the effectiveness of high-volume nasal steroid irrigations, 4 investigated safety, and 3 covered both. High-volume irrigations demonstrated superior efficacy in symptom improvement for CRS and AR compared to nasal sprays, particularly post-surgery. Budesonide was the most commonly used steroid. Safety evaluations indicated no significant hypothalamic-pituitary-adrenal axis suppression or increases in intraocular pressure, although minor adverse events were reported. High-volume steroid nasal irrigations are more effective than standard nasal sprays for CRS and AR, particularly post-surgery, without significant safety concerns. However, no studies on cost-effectiveness were found, suggesting a need for further research in this area.

A study on the interaction parameters of charged and uncharged radiation types with some indoor plants

This study investigates how gamma rays, neutrons, and electrons interact with five commonly found indoor plants: Spathiphyllum wallisii (SW), Ficus elastica (FE), Dieffenbachia camilla (DC), Schefflera arboricola (SA), and Ficus benjamina (FB). Utilizing experimental measurements (with HPGe detector), Monte Carlo simulations (GEANT4 and FLUKA), and theoretical calculations (ESTAR and WinXCOM), some radiation interaction parameters for gamma rays, fast neutrons, thermal neutrons, and electrons were determined. Secondary particle generation was also analyzed to provide a comprehensive assessment. The determined linear attenuation coefficients with the help of the WinXCOM are 0.1376, 0.1662, 0.1385, 0.1651 and 0.1698 cm-1 for SW, FE, DC, SA and FB, respectively. The calculated total macroscopic cross sections for indoor plants in the same sample order are 2.0290, 2.0350, 2.0285, 2.0363 and 2.0362 cm-1. Among the investigated plants, FB exhibited the highest gamma ray interaction, while SA and FB showed superior interaction against fast neutrons compared to SW and DC. The findings reveal significant variations in interaction effectiveness and secondary radiation production across these plants, offering valuable insights for radiation safety and environmental health evaluations.

Ratiometric fluorescent composites united metal-organic frameworks sensing system for detection of methyl-paraoxon

Organophosphorus pesticide residues pose significant risks to human health, but conventional analytical methods are costly and complex. To address this, we developed a new environmentally friendly technique using a simple hydrothermal method to create a ratiometric fluorescent composite (RFC) with two distinct signals: blue and orange. This RFC allowed for rapid detection and quantitative analysis of organophosphorus pesticides. The composite incorporated a cerium-based metal–organic framework (Ce-UiO-66), which could degrade methyl paraoxon (MP) due to the two oxidation states of cerium. The resulting degradation product, p-nitrophenol (p-NP), specifically quenched the blue fluorescence of the RFC via the inner filter effect (IFE), while the orange fluorescence remained unaffected, ensuring consistency under microenvironmental and spectrometer conditions. This innovative approach was sensitive, with a detection limit of 0.55 μM, selective, and repeatable, offering a new strategy for pesticide analysis and safety evaluation of edible and medicinal plant and water samples.

Pharmacokinetics-Based Safety Evaluation in Half-Dose Verteporfin Photodynamic Therapy

Introduction: This study was conducted to assess the systemic pharmacokinetic profiles of half-dose verteporfin photodynamic therapy (PDT) using concentration data from a previous clinical trial and to subsequently suggest safety precaution guidelines. Methods: Coefficients for the bi-exponential model were obtained from published data on post-infusion plasma verteporfin concentrations within a period of 0.17–4 h. Using the extrapolative forecasting method, we plotted the 48-h post-verteporfin plasma concentration model. The time required to achieve a comparable level of verteporfin 48 h after a conventional dose (6 mg/m2 body surface area, BSA) infusion was calculated for a half-dose infusion (3 mg/m2 BSA). Results: At 24 and 48 h post-verteporfin infusion, the plasma concentration following the conventional dose was 1.28 × 10−4 µg/mL and 5.06 × 10−8 µg/mL, compared to 3.57 × 10−5 µg/mL and 7.54 × 10−9 µg/mL for the half-dose PDT, representing concentrations that were 3.6 times and 6.7 times higher, respectively. The estimated time required to attain the same level of verteporfin 48 h after a conventional dose was calculated as 42-h post-half-dose PDT. Conclusions: The results of this study indicate that precautionary measures should be taken to avoid sunlight following both half and conventional doses of PDT during the similar post-treatment periods of two days. Nevertheless, given the substantially higher plasma concentration levels associated with conventional-dose PDT compared with the half-dose, systemic safety should be carefully considered when administering conventional-dose PDT.

Drug-induced torsadogenicity prediction model: An explainable machine learning-driven quantitative structure-toxicity relationship approach

Drug-induced Torsade de Pointes (TdP), a life-threatening polymorphic ventricular tachyarrhythmia, emerges due to the cardiotoxic effects of pharmaceuticals. The need for precise mechanisms and clinical biomarkers to detect this adverse effect presents substantial challenges in drug safety assessment. In this study, we propose that analyzing the physicochemical properties of pharmaceuticals can provide valuable insights into their potential for torsadogenic cardiotoxicity. Our research centers on estimating TdP risk based on the molecular structure of drugs. We introduce a novel quantitative structure-toxicity relationship (QSTR) prediction model that leverages an in silico approach developed by adopting the 4R rule in laboratory animals. This approach eliminates the need for animal testing, saves time, and reduces cost. Our algorithm has successfully predicted the torsadogenic risks of various pharmaceutical compounds. To develop this model, we employed Support Vector Machine (SVM) and ensemble techniques, including Random Forest (RF), Extreme Gradient Boosting (XGBoost), and Categorical Boosting (CatBoost). We enhanced the model's predictive accuracy through a rigorous two-step feature selection process. Furthermore, we utilized the SHapley Additive exPlanations (SHAP) technique to explain the prediction of torsadogenic risk, particularly within the RF model. This study represents a significant step towards creating a robust QSTR model, which can serve as an early screening tool for assessing the torsadogenic potential of pharmaceutical candidates or existing drugs. By incorporating molecular structure-based insights, we aim to enhance drug safety evaluation and minimize the risks of drug-induced TdP, ultimately benefiting both patients and the pharmaceutical industry.

Exploring the Therapeutic Potential of Sphenocentrum jollyanum Root Extract in Malaria Treatment: Efficacy, Safety, and Future Directions

Malaria remains a critical global health challenge, necessitating the exploration of novel therapeutic agents. This review examines the therapeutic potential of the ethanol root-extract of Sphenocentrum jollyanum, a plant traditionally used in West Africa for malaria treatment. Utilizing the Plasmodium berghei rodent model, which mirrors human malaria, we assess the extract’s efficacy in restoring haematological markers, safety profile, and potential as an adjunct or alternative therapy. Sphenocentrum jollyanum, known for its rich phytochemical composition, including alkaloids, flavonoids, saponins, tannins, and terpenoids, has demonstrated significant restorative effects in preliminary studies. The extract improved hemoglobin levels, red blood cell counts, and platelet counts in infected mice, indicating potential benefits in mitigating malaria-induced anemia and other haematological abnormalities. Its mechanisms of action include antioxidant, anti-inflammatory, and immunomodulatory effects. Despite its promising results, rigorous safety evaluations are necessary, including acute and chronic toxicity studies, to ensure its safe use. Future research should focus on clinical trials to validate efficacy, optimize dosage, and explore combination therapies with standard antimalarial drugs. The review emphasizes the need for standardized preparation methods, quality control, and integration into public health strategies to enhance malaria management, particularly in resource-limited regions. Keywords: Sphenocentrum jollyanum Root Extract, Malaria, Treatment, Efficacy, Safety.

Antidiabetic activity and Safety evaluation of Triticum aestivum (wheatgrass) extract in Alloxan-induced diabetic rats model.

Triticum aestivum (wheatgrasses) extract was studied for antidiabetic activity using alloxan-induced diabetes mellitus in rats. Triticum aestivum at 50, 100, and 200 mg/kg showed significant antidiabetic activity; it effected profound reductions in blood glucose over 28 days, especially the higher doses of 100 and 200 mg/kg, which were more effective than Glibenclamide. At 2000 mg/kg, the extract did not lower the blood glucose of normoglycemic rats- an indication of its safety and lack of hypoglycemic responses under non-diabetic conditions. It would appear that the antidiabetic activity of Triticum aestivum is through the protection and regeneration of beta cells that enhance insulin secretion, which in turn increases the utilization of glucose and normalizes carbohydrate, fat, and protein metabolism. This gradual lowering of blood glucose levels brought on by Triticum aestivum is clinically highly desired. The elicited antidepressant effect of Triticum aestivum was very likely due to its antioxidant effects and beta-cell regeneration activity. Thus, Triticum aestivum can meet the demand for a nontoxic, safe alternative to orthodox antidiabetic agents. Triticum aestivum, antidiabetic activity, alloxan-induced diabetes, insulin secretion, beta-cell regeneration, glucose metabolism, safety, and Glibenclamide.

Evaluation of the efficacy of combined immune checkpoint inhibitors in advanced melanoma treatment - Long term outcomes and emerging therapeutic perspectives: a narrative review

Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.

Ivacaftor for Chronic Obstructive Pulmonary Disease - Results from a Phase 2, Randomized Controlled Trial.

Patients with chronic obstructive pulmonary disease (COPD) exhibit acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR modulators may improve outcomes in patients with COPD, although recent data regarding magnitude of benefit have been inconclusive and effects on mucociliary clearance are unknown. We conducted a phase 2, randomized, double blind placebo control trial to determine safety and tolerability, and explore the potential mechanism of ivacaftor for the treatment of COPD. We randomized 40 patients with moderate to severe COPD and symptoms of chronic bronchitis to ivacaftor (N=30) or placebo (N=10) 150mg BID for 12 weeks. Primary endpoints included evaluation of safety of ivacaftor and pharmacokinetics (PK). Secondary endpoints included measures of CFTR activity and clinical outcomes. Ivacaftor was safe and tolerable with similar rates of adverse events rates between groups. Most common adverse event was diarrhea in the ivacaftor group and acute COPD exacerbation in the placebo group. PK analysis found the mean area under the curve over 12 hours (AUC12) to be 72% of the previously reported AUC12 in cystic fibrosis (CF). Treatment with ivacaftor did not improve sweat chloride, whole lung mucociliary clearance, lung function or respiratory symptoms. Ivacaftor was safe and well tolerated, but did not improve measures of CFTR activity or mucus clearance. As serum concentrations achieved were lower than observed in CF at the same dose, and modulation of wild type CFTR differs from G551D, further dose determination studies are needed to better understand treatment efficacy of CFTR potentiators in COPD. Clinical trial registration available at www. gov, ID: NCT03085485.

Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors

During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.