Toxicity Profile Research Articles

Toxicity profile and clinical outcomes of stereotactic body radiotherapy with afocal boost without fiducials or perirectal hydrogel spacer for localized prostate cancer.

Whole-prostate dose escalation in stereotactic body radiotherapy (SBRT) for localized prostate cancer (PCa) can improve oncological outcomes, albeit at the cost of increased toxicity. Afocal boost to the dominant intraprostatic lesion (DIL) is gaining interest as an alternative approach. Herein, we investigate the safety and efficacy of this approach. This retrospective study enrolled patients with localized PCa who underwent five-fraction SBRT with afocal boost to the DIL at our institution between May 2016 and August 2021. The prescription doses to the whole prostate were 35 and 36.25 Gy for low- to favorable intermediate-risk PCa and unfavorable intermediate- to high-risk PCa, respectively. The focal boost to the DIL was up to 115-140% of the prescribed dose. None of the patients underwent pretreatment fiducial or perirectal hydrogel spacer placement. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities and oncological outcomes were assessed. Among the 520 patients, 44% were categorized as patients with high-risk PCa. The median follow-up period was 42.9months. No acute or late grade ≥3 toxicities were observed. Acute and late grade2 GU toxicities were observed in 22.3 and 6.1%, respectively, while GI toxicities were observed in 2.1 and 0.8% of the patients. The 4‑year relapse-free survival rate was 94.8% among all patients. Our results indicate that SBRT with afocal boost without fiducials or perirectal hydrogel spacer for localized PCa has apromising toxicity profile and oncological outcomes. Longer follow-up studies are necessary to adequately evaluate late toxicities and efficacy.

Novel bioabsorbable, low-dose rate brachytherapy device (CivaSheet®) with radical prostatectomy and adjuvant external beam radiation for the management of prostate cancer.

To investigate the safety and cancer control of a novel bioabsorbable, low-dose rate brachytherapy device, CivaSheet® (CivaTech Oncology Inc., Durham, NC, USA), in combination with radical prostatectomy (RP) with or without adjuvant external beam radiation therapy (EBRT) for the management of prostate cancer (PCa). This is an initial, single-centre experience, two-dose level, two-stage study conducted on patients with intermediate- and high-risk PCa. The CivaSheet was implanted during RP, followed by adjuvant EBRT in patients with adverse pathological features. Toxicities and peri- and postoperative complications were assessed. Biochemical recurrence (BCR) at the 6-month follow-up after EBRT was also evaluated. Six patients were enrolled, with a median (range) age of 56 (53-71) years. No intraoperative complications occurred. No dose-limiting toxicities were observed at a maximum tested dose of 75 Gy. BCR occurred in one patient at 6 months, while another patient had residual disease and metastasis at 6 months. All patients reported having postoperative erectile dysfunction and one patient experienced urinary incontinence after EBRT. This study demonstrated the feasibility and safety of CivaSheet combined with RP and adjuvant EBRT for high-risk PCa. The short-term toxicity profile was well-tolerated, supporting further prospective evaluation with clinical trials.

Concomitant Inhibition and Collaring of Dual-Species Biofilms Formed by Candida auris and Staphylococcus aureus by Triazole Based Small Molecule Inhibitors

Background/Objectives: Biofilm-associated infections, particularly those involving Candida auris and Staphylococcus aureus, pose significant challenges in clinical settings due to their resilience and resistance to conventional treatments. This study aimed to synthesize novel triazole derivatives containing a piperazine ring via click chemistry and evaluate their efficacy in disrupting biofilms formed by these pathogens. Methods: Triazole derivatives were synthesized using click chemistry techniques. The antimicrobial activity of the compounds was tested against planktonic cells of C. auris and S. aureus in single and dual-species culture conditions. Biofilm disruption efficacy was assessed, alongside the evaluation of physicochemical properties, oral bioavailability potential, and toxicity profiles. Results: The compound T3 demonstrated potent antimicrobial activity against planktonic cells of C. auris and S. aureus in both single and dual-species cultures. T3 exhibited significant efficacy in reducing microbial viability within biofilms formed by these pathogens. Physicochemical analyses revealed favorable solubility and permeability profiles, supporting its potential for oral bioavailability. Toxicity assessments showed a non-toxic profile, highlighting a promising safety margin for further development. Conclusions: This study underscores the anti-biofilm properties of novel triazole-piperazine derivatives, particularly T3, against single and dual-species biofilms of C. auris and S. aureus. These findings position T3 as a promising candidate for developing therapies targeting polymicrobial infections and provide a foundation for future research into alternative strategies for combating biofilm-associated infections.

Efficacy and safety of adding immune checkpoint inhibitors to first-line standard therapy for recurrent or advanced cervical cancer: a meta-analysis of phase 3 clinical trials

BackgroundImmune checkpoint inhibitors (ICIs) combined with standard therapy (ST) have emerged as a novel treatment strategy for recurrent or advanced cervical cancer (r/a CC). However, the available data from phase 3 clinical trials have yielded mixed results. This study aims to evaluate the therapeutic efficacy and safety of adding ICIs to ST in the treatment of r/a CC.MethodsData from four phase 3 clinical trials (KEYNOTE-826, CALLA, BEATcc, and ENGOT-cx11/GOG-3047/KEYNOTE-A18), involving 2,857 patients, were analyzed. Meta-analyses were conducted to combine hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) for the objective response rate (ORR), and relative risks (RRs) for adverse events (AEs).ResultsThe addition of ICIs to ST significantly improved PFS (HR, 0.67; 95% CI, 0.60-0.75), OS (HR, 0.66; 95% CI, 0.58-0.75), and ORR (OR, 1.48; 95% CI, 1.13-1.94) compared to ST alone. However, there was a modest increase in grade 3-5 AEs (RR, 1.08; 95% CI, 1.03-1.13) with the combined therapy.ConclusionThis meta-analysis indicates that the combination of ICIs with ST in the treatment of r/a CC not only demonstrates superior efficacy over ST alone but also maintains a comparable toxicity profile, offering strong evidence for an effective and relatively safe treatment approach for managing this disease.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024593895.

Concurrent immunotherapy and radiation in cisplatin-ineligible patients with HNSCC: a systematic review & meta-analysis.

Head and squamous cell carcinoma (HNSCC) in the locally advanced setting is challenging to treat and remains an area of significant morbidity and mortality. For patients who are cisplatin-ineligible and considered unresectable, there is no clear standard of care including the choice of radiosensitizer. OVID Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched. Randomized clinical trials (RCTs) of cisplatin-ineligible unresectable HNSCC patients who were randomized to an immune checkpoint inhibitor concurrent with radiation compared to a control arm were included. Data was pooled and assessed using a random-effects model for the meta-analysis. Three eligible RCTs were identified and analyzed which comprised 594 patients whose median age ranged from 65-72 years. There was no difference in overall survival (pooled HR 1.02, 95% CI 0.76-1.37, p = 0.88) or PFS (pooled HR 0.92, 95% CI 0.68-1.23, p = 0.56). Grade greater than or equal to 3 adverse events were favored to be less in the immunotherapy arm. Immune-checkpoint inhibitors are not superior to cetuximab when used with definitive radiation in HNSCC. Further study is warranted, given its potential signal for non-inferior survival with less toxicity profile trends.

Nanomedicine in the treatment of Alzheimer's disease: bypassing the blood-brain barrier with cutting-edge nanotechnology.

Alzheimer's disease (AD) remains a formidable challenge in the field of neurodegenerative disorders, necessitating innovative therapeutic strategies. Nanomedicine, leveraging nanomaterials, has emerged as a promising avenue for AD treatment, with a key emphasis on overcoming the blood-brain barrier (BBB) to enhance drug delivery efficiency. This review provides a comprehensive analysis of recent advancements in the application of nanomaterials for AD therapy, highlighting their unique properties and functions. The blood-brain barrier, a complex physiological barrier, poses a significant hurdle for traditional drug delivery to the brain. Nanomedicine addresses this challenge by utilizing various nanomaterials such as liposomes, polymeric nanoparticles, and metal nanoparticles. These nanocarriers enable improved drug bioavailability, sustained release, and targeted delivery to specific brain regions affected by AD pathology. The review discusses the diverse range of nanomaterials employed in AD treatment, exploring their capacity to encapsulate therapeutic agents, modulate drug release kinetics, and enhance drug stability. Additionally, the multifunctionality of nanomaterials allows for simultaneous imaging and therapy, facilitating early diagnosis and intervention. Key aspects covered include the interaction of nanomaterials with Aβ aggregates, the role of antioxidants in mitigating oxidative stress, and the potential of nanomedicine in alleviating neuroinflammation associated with AD. Furthermore, the safety, biocompatibility, and toxicity profiles of various nanomaterials are scrutinized to ensure their clinical applicability. In conclusion, this review underscores the pivotal role of nanomedicine and nanomaterials in revolutionizing AD treatment strategies. By specifically addressing BBB challenges, these innovative approaches offer new avenues for targeted drug delivery and improved therapeutic outcomes in the complex landscape of Alzheimer's disease.

Toxicity profiles of immunochemotherapy for gastric or gastroesophageal junction adenocarcinoma: a systematic review and meta-analysis.

Neoadjuvant immunochemotherapy is emerging as a promising regimen for patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. However, it remains unclear whether immunochemotherapy will bring more adverse events (AEs) leading to a delay or even cancellation of surgeries. We aimed to provide a comprehensive analysis of the toxicity profiles for immune checkpoint inhibitors (ICIs) combined with chemotherapy among patients with G/GEJ adenocarcinoma. Published trials up to January 2024 were identified on Web of Science, Cochrane Library, Embase, and PubMed. Single-group and controlled clinical trials with ICIs in combination with chemotherapy in patients with G/GEJ adenocarcinoma were included. Two reviewers independently extracted data including incidence rate of AEs. The primary outcomes included the proportion of patients with adverse events leading to treatment discontinuation, grade 3 or higher adverse events, and serious adverse events. This study is registered with PROSPERO (CRD42023492676). Twenty studies were included for a total of 6692 patients. In patients receiving immunochemotherapy, 17% (95% confidence interval (CI), 11-23%) had adverse events leading to treatment discontinuation, 23% (95% CI, 19-27%) had serious adverse events, and 64% (95% CI, 58-70%) had grade 3 or higher adverse events. Compared with patients receiving chemotherapy alone, patients with immunochemotherapy were associated with higher rates of adverse events leading to discontinuation (RR, 1.45; 95% CI, 1.32-1.60), serious adverse events (RR, 1.27; 95% CI, 1.04-1.57), and grade 3 or higher adverse events (RR, 1.15; 95% CI, 1.07-1.23). In conclusion, the incidence of adverse events leading to discontinuation, serious adverse events, and grade 3 or higher adverse events were higher in patients receiving immunochemotherapy compared to those with chemotherapy.

Cell Painting: a decade of discovery and innovation in cellular imaging.

Modern quantitative image analysis techniques have enabled high-throughput, high-content imaging experiments. Image-based profiling leverages the rich information in images to identify similarities or differences among biological samples, rather than measuring a few features, as in high-content screening. Here, we review a decade of advancements and applications of Cell Painting, a microscopy-based cell-labeling assay aiming to capture a cell's state, introduced in 2013 to optimize and standardize image-based profiling. Cell Painting's ability to capture cellular responses to various perturbations has expanded owing to improvements in the protocol, adaptations for different perturbations, and enhanced methodologies for feature extraction, quality control, and batch-effect correction. Cell Painting is a versatile tool that has been used in various applications, alone or with other -omics data, to decipher the mechanism of action of a compound, its toxicity profile, and other biological effects. Future advances will likely involve computational and experimental techniques, new publicly available datasets, and integration with other high-content data types.

Cytotoxic Effects of ZnO and Ag Nanoparticles Synthesized in Microalgae Extracts on PC12 Cells

The green synthesis of silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs), as well as Ag/Ag2O/ZnO nanocomposites (NCs), using polar and apolar extracts of Chlorella vulgaris, offers a sustainable method for producing nanomaterials with tunable properties. The impact of the synthesis environment and the nanomaterials’ characteristics on cytotoxicity was evaluated by examining reactive species production and their effects on mitochondrial bioenergetic functions. Cytotoxicity assays on PC12 cells, a cell line originated from a rat pheochromocytoma, an adrenal medulla tumor, demonstrated that Ag/Ag2O NPs synthesized with apolar (Ag/Ag2O NPs A) and polar (Ag/Ag2O NPs P) extracts exhibited significant cytotoxic effects, primarily driven by Ag+ ion release and the disruption of mitochondrial function. However, it is more likely the organic content, rather than size, influenced anticancer activity, as commercial Ag NPs, despite smaller crystallite sizes, exhibit less effective activity. ZnO NPs P showed increased reactive oxygen species (ROS) generation, correlated with higher cytotoxicity, while ZnO NPs A produced lower ROS levels, resulting in diminished cytotoxic effects. A comparative analysis revealed significant differences in LD50 values and toxicity profiles. Differentiated PC12 cells showed higher resistance to ZnO, while AgNPs and Ag/Ag2O-based materials had similar effects on both cell types. This study emphasizes the crucial role of the synthesis environment and bioactive compounds from C. vulgaris in modulating nanoparticle surface chemistry, ROS generation, and cytotoxicity. The results provide valuable insights for designing safer and more effective nanomaterials for biomedical applications, especially for targeting tumor-like cells, by exploring the relationships between nanoparticle size, polarity, capping agents, and nanocomposite structures.

Biological insights and therapeutic potential of Glycyrrhiza uralensis and its bioactive compounds: an updated review.

The recent resurgence of traditional medicines, driven by a renewed interest in the medicinal use of plant extracts, has garnered significant scientific attention for their therapeutic efficacy in treating a wide range of diseases. Glycyrrhiza species, commonly known as licorice, are widely recognized both as herbal remedies and as natural sweeteners. Among these, Glycyrrhiza uralensis stands out for its exceptional therapeutic potential, particularly in enhancing muscle regeneration, slowing muscle aging, and promoting skeletal muscle myogenesis. This review explores the traditional uses and biological effects of G. uralensis, highlighting the biological significance of its bioactive constituents, such as saponins and flavonoids. The hepatoprotective, antibacterial, antioxidant, anticancer, antidiabetic, antiobesity, anti-inflammatory, skeletal muscle-enhancing and cardiovascular effects of G. uralensis are reviewed, along with its toxicity and safety profile. Additionally, we propose directions for future clinical and scientific investigations, advocating for using G. uralensis as a natural therapeutic agent. The primary aim of this review is to contribute to the incorporation of this ancient medicine into modern clinical practice.

Novel Tgase2 Allosteric Site Inhibitors: A Computational Study

Tranglutaminase-2 (Tgase2) is one of the primary Transglutaminase enzyme family members having a significant role in Ca2+ -dependent and -independent post-translational modifications. It has been previously reported that Tgase2 has significant regulatory roles over metabolic functions such as signaling pathways, inflammatory response, and wound healing. In particular, many cancer types’ prognosis includes over Tgase2 activity since it might induce metastasis through regulating crosslinking of extracellular matrix (ECM) proteins, and tumor proliferation via leading spheroid formation. Considering these fundamentals, discovery of novel chemical compounds to inhibit Tgase2 activity might be a strong approach in cancer treatment. Furthermore, it’s known that Tgase2 activity might be inhibited through blocking its allosteric site with chemical compounds. As such, a drug library including 12,111 small compounds were virtually screened to allosteric site of Tgase2. The study has been validated by repetition the strategy with previously discovered inhibitors. Allosteric and active sites of Tgase2 have been demonstrated with protein-protein docking technique. Eventually, recently discovered ligands have been characterized according to their ADME and toxicity profiles. Results have demonstrated that Eltrombopag, Talniflumate, and Lumacaftor drugs might be repurposed in the inhibition of Tgase2 since that they exhibit high binding affinity, ADME, and toxicity properties comparing the known inhibitors.

Chemical Composition, Antibacterial, Antioxidant, and Toxicity Profiles of Cajuput Oils from Diverse Malaysian Districts

Chemical Composition, Antibacterial, Antioxidant, and Toxicity Profiles of Cajuput Oils from Diverse Malaysian Districts

Do Anticancer Medicinal Compounds have DNMT1 Regulating Activity: An In silico Investigation

Background: DNA methyltransferases (DNMTs) are a group of epigenetic enzymes implicated in regulating gene expression in actively dividing cells. Among these enzymes, DNMT1 plays a leading role in causing increased DNA methylation of tumor suppressors and other genes in cancer cells. This methylation event disrupts the cell cycle regulating genes, allowing an uninterrupted proliferation of cancer cells, and stimulating the inhibition of the degradation of proteins and aberrant transcription activation. Cytosine analog drugs have been shown to reduce DNA methylation but provoke the expression of other prometastatic genes. On the other hand, medicinal compounds act similarly to cytosine analogs by reducing the expression and activity of DNMT1, as reported in some in vitro cancer studies. However, it remains a mystery what those promising medicinal compounds are that show such activity. Objectives: The objective of this study was to screen medicinal compounds that reduce the expression and interact with the active site residues of DNMT1. Methods: To analyze medicinal compounds against DNMT1, two in silico tools were employed: DIGEP-pred and IGEMDOCK to discover and identify 98 lead medicinal compounds having anticancer potential, capable of regulating DNMT1 expression and activity. Results: Our results have identified twenty (20) medicinal compounds that reduced the expression of DNMT1 up to 50-77% as compared to the standard cytosine analog (91.5%). These compounds have also interacted with the reported active site residues of DNMT1, as predicted by IGEMDOCK. These compounds have adequate druglikeness, toxicity, and pharmacokinetic properties as described by Protox-II and ADMET lab 2.0. Conclusion: Thus, our study provides an initial report of those medicinal compounds that have DNMT1 targeting ability and have a relatively safer pharmacokinetic and toxicity profile.

A Competition-Based Strategy for the Isolation of an Anti-Idiotypic Blocking Module and Fine-Tuning for Conditional Activation of a Therapeutic Antibody.

The masking of therapeutic antibodies by the installation of a blocking module that can be removed under certain physiological conditions, is becoming increasingly important to improve their safety and toxicity profile. To gain access to such masking units, we used chicken immunization in combination with yeast surface display and a competition-based FACS screening campaign to obtain anti-idiotypic single-chain Fv (scFv) fragments. This approach promotes the identification of functional masking units, since specificity and high affinity do not necessarily guarantee a paratope blocking effect. This strategy was used to isolate a scFv masking unit for the therapeutic antibody 6G11 (BI-1206), which is currently in clinical trials for the treatment of B-cell lymphoma to block the inhibitory Fcγ receptor IIB (CD32b). N-terminal fusion of the anti-idiotypic scFv to the 6G11 light chain successfully abolished binding to FcγRIIB in vitro. For conditional activation, a cleavable linker for the tumor-associated protease MMP-9 was implemented. To improve demasking efficiency, the affinity of the scFv mask was attenuated through rational design. The substitution of one key amino acid in the masking scFv reduced the affinity toward the 6G11 paratope by factor 10 but still mediated 9800-fold blocking of receptor binding. Proteolytic demasking allowed full recovery of therapeutic antibody function in vitro, supporting the concept of conditional antibody activation using this anti-idiotypic binding module.

Antiviral Drug Discovery with an Optimized Biochemical Dengue Protease Assay: Improved Predictive Power for Antiviral Efficacy

The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverse N-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.

Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Final Results of the ORATOR Randomized Trial.

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation). The primary end point was swallowing quality of life (QOL) assessed with the MD Anderson Dysphagia Inventory (MDADI). Secondary end points included overall and progression-free survival (OS, PFS), adverse events (AEs), and other QOL metrics. The primary end point has been previously reported (Nichols 2019). In this report, the median follow-up was 5.1 years (IQR, 5.0-5.3 years). MDADI total scores converged by 5 years and were not significantly different across the follow-up period (P = .11). EORTC QLQ-C30 and H&N35 scores demonstrated differing profiles, including worse dry mouth in the RT arm (P = .032) and worse pain in the TORS arm (P = .002). Grade 2-5 AE rates did not differ between arms (91% [n = 31] v 97% [n = 33] respectively, P = .61), with more neutropenia and hearing loss in the RT arm, and more dysphagia and other pain in the TORS arm based on grades 2-5 (all P < .05). There were no differences in OS or PFS. In conclusion, toxicity and QOL profiles differ in some domains between RT and TORS, but oncologic outcomes were excellent in both arms. Choice of treatment should remain a shared decision between the patient and their providers.

Computer-assisted discovery of tyrosinase inhibitors from turmeric and clove: An in silico study on natural skin whitening agents and their potential toxicity

A computational approach was employed to identify potential tyrosinase-related protein 1 (TYRP1) inhibitors from turmeric and clove extracts, with the goal of discovering safer alternatives to the toxic hydroquinone for skin whitening applications. Gas Chromatography–Mass Spectrometry (GC–MS) analysis revealed the phytochemical composition of the plant extracts, which were then evaluated for their binding affinity to TYRP1 through molecular docking simulations. The stability of the resulting hit compounds was assessed via molecular dynamics simulations, and their dermal toxicity profiles were determined using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Density Functional Theory (DFT) calculations were also performed to compare the chemical reactivity of the hit compounds to hydroquinone. The results identified 3,4-dimethoxybenzamidoxime from clove and Ar-turmerone from turmeric as potential inhibitors, exhibiting binding free energies of −6.8 kcal/mol and −6.6 kcal/mol, respectively. These values surpass those of hydroquinone (−5.1 kcal/mol) and the native ligand (−5.5 kcal/mol), suggesting potential inhibitory activity. Notably, 3,4-dimethoxybenzamidoxime exhibited favorable skin permeation properties and passed all toxicity tests, suggesting its potential as a safe and effective replacement for hydroquinone in skin whitening products.

Glacium flavum‐Derived Phytochemical Compounds and Their Molecular Interactions with SIRT1

AbstractThis study investigates the antioxidant activity, phenolic content, and phytochemical components of Glacium flavum root extract. The DPPH radical scavenging activity was found to be 87.01 µg/mL ± 4.98, iron chelating activity 7.49 mg/mL ± 0.36, total phenolic content 594.39 mg GAE/g extract ± 17.90, and total flavonoid content 44.30 mg QE/g extract ± 4.76. These results indicate that G. flavum root extract possesses significant antioxidant properties and rich phytochemical components. Gas chromatography–mass spectrometry (GC–MS) analysis identified 11 biologically active components. Fatty acid composition analysis revealed lauric acid (1.26%), myristic acid (1.20%), palmitic acid (14.58%), stearic acid (3.40%), oleic acid (4.41%), linoleic acid (20.00%), and alpha‐linolenic acid (41.43%). Molecular docking studies demonstrated significant binding interactions of alpha‐linolenic acid and ethyl oxirane‐2‐carboxylate with the SIRT1 catalytic domain (4I5I), with binding energies of −4.5 kcal/mol and −4.2 kcal/mol, respectively. Additionally, (2S)‐2‐hydroxybutanedioic acid and butane‐2,3‐diol also exhibited notable interactions. Toxicity profiles showed that alpha‐linolenic acid and butane‐2,3‐diol have lower toxicity, while 2‐ethyl oxirane‐2‐carboxylate and (2S)‐2‐hydroxybutanedioic acid displayed moderate toxicity. Drug‐likeness evaluations indicate that the compounds meet various medicinal chemistry criteria, each facing development challenges. Overall, this study provides a comprehensive overview of the antioxidant potential, biologically active components, and toxicological characteristics of G. flavum root extract.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Abiraterone Clinical Trials

Purpose: Our study aimed to evaluate the risk and benefit profiles of clinical trials using abiraterone in cancer treatment.Materials and Methods: A comprehensive search was conducted on May 24, 2023, using databases such as PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov. We extracted data on adverse events, progression-free survival, overall survival, objective response rate (ORR), and prostate-specific antigen response rate (PSA-RR). The Common Terminology Criteria for Adverse Events were used to assess risks, while ORR and PSA-RR were used to assess benefits. Trials were categorized as positive, negative, or indeterminate based on their safety profiles and efficacy outcomes.Results: Nearly all clinical trials testing abiraterone in prostate cancer showed promising outcomes with 89% of studies meeting their endpoint. Our study supports abiraterone’s use in prostate cancer, its only U.S. Food and Drug Administration-approved indication to treat, with a median ORR of 20.0% and a median PSA-RR of 42.0%. However, when looking at the 3 novel indications tested, the risk-to-benefit profile was similar to that of its original approval. Even though most novel indications failed to meet their primary endpoint, the overall toxicity profile was similar to that found in prostate cancer.Conclusion: Abiraterone showed an overall risk-to-benefit portfolio that supports the use of its treatment in prostate cancer. Although the primary endpoints in ovarian and breast cancer trials were not met, the use was appropriate when assessing how the mechanism of action for abiraterone could be beneficial in patients with these types of cancers.

Asoprisnil as a Novel Ligand Interacting with Stress-Associated Glucocorticoid Receptor

Background/objective: The glucocorticoid receptor (GR) is critical in regulating cortisol production during stress. This makes it a key target for treating conditions associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation, such as mental disorders. This study explores novel ligands beyond mifepristone for their potential to modulate GR with improved efficacy and safety. By investigating these interactions, we seek to identify new pharmacotherapeutic options for stress-related mental illness. Methods: The ligands asoprisnil, campestanol, and stellasterol were selected based on structural similarities to mifepristone (reference ligand) and evaluated for pharmacological and ADME (absorption, distribution, metabolism, and excretion) properties using the SwissADME database. Molecular docking with AutoDock 4.2.6 and molecular dynamics simulations were performed to investigate ligand–protein interactions with the human glucocorticoid receptor, and binding free energies were calculated using MMPBSA. Results: Pharmacokinetic analysis revealed that asoprisnil exhibited high gastrointestinal absorption and obeyed Lipinski’s rule, while mifepristone crossed the blood–brain barrier. Toxicological predictions showed that mifepristone was active for neurotoxicity and immunotoxicity, while asoprisnil, campestanol, and stellasterol displayed lower toxicity profiles. Asoprisnil demonstrated the highest stability in molecular dynamics simulations, with the highest negative binding energy of −62.35 kcal/mol, when compared to mifepristone, campestanol, and stellasterol, with binding energies of −57.08 kcal/mol, −49.99 kcal/mol, and −46.69 kcal/mol, respectively. Conclusion: This makes asoprisnil a potentially favourable therapeutic candidate compared to mifepristone. However, further validation of asoprisnil’s interaction, efficacy, and safety in stress-related mental disorders through experimental studies and clinical trials is needed.