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Cytochrome P450 (CYP450) enzymes are the most important phase I drug-metabolizing enzymes in humans, and regulation of their activity is directly related to drug efficacy and safety. As herbal medicines gain worldwide popularity, their concurrent use with drugs has become more common. The effect of phytochemicals from herbal sources on CYP450 activity is a critical factor contributing to clinical drug interactions. When CYP450 activity is inhibited, it is easy to cause the accumulation of substrate drugs and cause toxic side effects, or the formation of toxic intermediates due to altered metabolic pathways, which seriously threaten the medication safety of patients. However, only a limited number of herbs have been evaluated for their impact on CYP450 enzyme activity, and data on the inhibitory effects of key CYP450 isoforms involved in drug metabolism remain scarce. Particularly noteworthy is the lack of research on the mechanisms of herb-drug interactions (HDIs) and the constituents of compound herbs, which impedes comprehensive identification and evaluation of potential clinical risks. This paper provides a systematic summary of CYP450 phytochemical inhibitors such as alkaloids, quinones, flavonoids, terpenoids, and coumarins in herbal medicine. In addition to the common CYP450 isoforms (e.g., CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), this review also focuses on some less frequently studied isoforms, including CYP1B1, CYP7A1, CYP8B1, CYP17A1, and CYP19A1. Through an in-depth analysis of the current research limitations, this study proposes targeted directions for technological innovation and research standardization, thereby providing a scientific basis for addressing the research gap in HDIs and herb-herb interactions (HHIs) and formulating strategies for the rational use of herbs and standards for safety evaluation.
Ferrocene, which was a milestone organometallic compound discovered in 1951, remains of interest in medicinal chemistry due to its exceptional stability, redox activity, and ease of functionalization, etc. A variety of pharmacological activities were observed for the Ferrocene derivatives, and several reviews have appeared highlighting the increasing applications of Ferrocene in bio-organometallic chemistry. Novel ferrocene-conjugates of betulin, artemisinin, steroids, and alkaloids were reported, which showed enhanced biological potential. Notably, ferroquine is still in Phase IIb clinical trials, and a number of ferrocene-based anticancer agents demonstrate activity against multidrug resistance. Ferrocene, thus, is an ideal scaffold for next-generation therapeutics with unique structural and redox properties that will overcome current limitations of drug scaffolds. The methodology consists of a thorough literature survey of chemistry, structural modifications, pharmacological activities, pharmacokinetics, toxicity, and future prospects of compounds involving ferrocene. Recent developments on anticancer, antimalarial, antibacterial, and antiinflammatory applications with detailed Structure Activity Relationship (SAR) were highlighted. The results show that drug lipophilicity, cellular uptake, and redox activity are improved by the integration of ferrocene, which results in improved efficacy and resistance-overcoming ability. The main pharmaceutical results to date are the preparation of a successful antimalarial drug called ferroquine and a number of ferrocene derivatives with strong anticancer activity. Pharmacokinetic analysis shows good absorption, distribution, and metabolic stability, and the toxicity studies highlight the need for redox tuning to reduce side effects. New approaches such as prodrug design, targeting with nanoparticles, PEGylation, and targeted conjugates help overcome issues of solubility, selectivity, and safety. Ferrocene-based drug molecules are versatile and promising metallopharmaceuticals. It is hoped that ongoing interdisciplinary research and innovative delivery methods will further extend their clinical utility, especially in the treatment of multidrug resistance and their use in central nervous system and metabolic diseases. Ferrocene-based drug molecules exhibit remarkable potential in medicinal chemistry with respect to their stability, redox activity, and structural versatility. Their inclusion makes them more lipophilic, increases their uptake into cells, and improves their activity, especially in the fields of anticancer and antimalarial activity, as reflected in the discovery of Ferroquine as a milestone in the clinical field. The targeted delivery and prodrug approaches also further enhance safety and pharmacokinetic properties. In conclusion, ferrocene can be used as a good scaffold in the design of second-generation drugs that can overcome drug resistance.
Drug discovery remains constrained by high attrition rates and the fragmented evaluation of exposure, efficacy, and safety. Mechanistic models offer a biologically grounded framework for connecting these determinants across multiple levels of biological organization. This may help improve translational decision-making by supporting earlier and more integrated assessment of candidate progression. This narrative review examines the conceptual basis and current role of next-generation mechanistic models in drug discovery, with emphasis on physiologically based pharmacokinetic models, virtual cell-based assays, quantitative systems pharmacology, artificial intelligence (AI)-augmented mechanistic models, and emerging virtual-cell frameworks. It highlights how these approaches may connect efficacy and safety across biological scales, support in vitro-to-in vivo extrapolation, incorporate in silico predictions, and improve candidate prioritization. The literature was surveyed through PubMed searches conducted up to 25 May 2026. Next-generation mechanistic models are unlikely to transform drug discovery simply by increasing biological detail or computational sophistication. Progress in this direction will depend on standardized data streams, robust validation, explicit model calibration, reproducibility, tighter integration between models, and careful alignment between model design and context of use. Under these conditions, mechanistic frameworks may become important components of a more predictive and less attrition-prone drug discovery pipeline.
Advanced colorectal cancer (CRC) has limited therapeutic options. Antibody-drug conjugates (ADCs) deliver cytotoxic agents selectively, minimizing systemic toxicity. This study outlines the current clinical trial landscape of ADCs in CRC to identify research gaps and future directions. We queried the Trialtrove database (up to August 2025) for non-observational trials of ADCs in CRC. Analytical indicators included temporal trends, geographic distribution, sponsor type, target antigens, and payloads. Overall, 194 eligible trials were identified. Trial numbers have steadily increased since 2020, peaking in 2024. Most are open trials, predominantly conducted in China and the United States, and heavily industry-sponsored. HER2, Trop-2, and c-Met are the most frequently studied targets. Topoisomerase I inhibitors are the most common payloads, frequently paired with cleavable linkers. Crucially, the vast majority of these trials remain in early phases (Phase I/II), with Safety and tolerability remaining the primary endpoints. ADCs show preliminary therapeutic potential in CRC; however, assertions regarding broad efficacy must remain highly cautious given the early-stage, safety-oriented nature of the current pipeline. Furthermore, the current landscape faces challenges such as publication bias and industry dominance, which prioritize commercially viable hotspots over niche targets. Future progress relies on discovering novel targets, optimizing linker-payload designs, and exploring rational combination therapies.
Accurate prediction of adverse drug reactions (ADRs) is essential for drug safety surveillance, and recent advances in machine learning with heterogeneous biomedical information have improved predictive performance. However, two challenges remain: current methods often learn inadequate ADR representations that fail to capture dependencies among ADRs, and generalize poorly to novel drugs. To obtain informative ADR embeddings, we construct a multi-source, multi-relational ADR graph that integrates hierarchical structure and empirical ADR co-occurrence, and apply a relational graph convolutional network (R-GCN) to learn relation-aware ADR representations. To enhance generalization to novel drugs, we exploit the hierarchical structure of the Anatomical Therapeutic Chemical (ATC) classification to link drugs via shared higher-level categories for effective knowledge transfer and model these relations with an R-GCN. We further introduce a Conditional Domain Adversarial Network (CDAN) to reduce distribution shifts between known and novel drugs by aligning features conditioned on predicted ADR labels, learning domain-invariant yet task-relevant representations. Additionally, to exploit similar ADR patterns among related drugs, we introduce a dual-branch mixture-of-experts (Dual-MoE) module where each expert captures ADR commonalities within a drug category in one branch, while a separate branch models global patterns. Extensive experiments show that our method consistently outperforms seven baselines, achieving F1 improvements of 4.3% and 4.7% over the best baseline on two datasets, respectively, with more balanced precision-recall trade-offs. It also improves AUC on uncommon ADRs by 7% more than on common ADRs, and remains more robust under data sparsity, with more gradual performance degradation as training data decreases. The code of our model is available at https://github.com/fzsdb/Knowledge-guided-ADR-prediction.git.
Drug repurposing involves the discovery of new therapeutic uses of existing drugs that have already been approved by the regulatory authorities. It provides an alternative with more efficient approaches to traditional drug discovery, leveraging already known safety profiles, shortened development and financial costs. Current advances in computational biology, artificial intelligence and big-data analytics have expanded the range of opportunities for systematic repurposing, but the successful translation of these opportunities is increasingly dependent on the holistic input of medicinal chemistry. The therapeutic relevance of medicinal chemistry-guided repurposing is being investigated over a range of unmet medical conditions, such as complicated diseases, rare diseases and new health crises, such as the COVID-19 pandemic. In this review, we underscore the critical importance of medicinal chemistry, including structure-activity relationship analysis, molecular optimization, target engagement assay, and ADMET refinement, in supporting the efficacy and safety of repurposed candidates. We further discuss the co-existence of these strategies with in silico predictions of the target, virtual screening, and phenotypic assays to narrow down lead compounds and improve translational success. Additionally, the role of medicinal chemistry in personalized medicine is also taken into account, where special attention is paid to the possibility of modifying pharmacological characteristics to patient-specific molecular and biological phenotypes. The study aims to encourage researchers and clinicians to adopt the revolutionary potential of drug repurposing to enhance treatment decisions and overall health outcomes among a large number of patients. Moreover, in a medical landscape that is becoming more complex, drug repurposing can transform the pharmaceutical industry, accelerate the process of making viable therapy available, and facilitate the delivery of quality healthcare.
Major depressive disorder is a leading cause of disability worldwide, with significant challenges in treatment response, adherence and functional recovery. Despite the availability of numerous antidepressants, a substantial proportion of patients fail to achieve remission with initial therapy, underscoring the need for effective first-line treatment options. Desvenlafaxine, a serotonin-noradrenaline reuptake inhibitor, has demonstrated efficacy and safety in major depressive disorder, while its pharmacokinetic properties result in minimal drug-drug interactions. This narrative review evaluates clinical evidence supporting the use of desvenlafaxine as a first-line treatment and examines patient subgroups that may benefit most from this antidepressant. A comprehensive literature review was conducted to evaluate the evidence on desvenlafaxine in the treatment of major depressive disorder. This was supplemented by clinical insights discussed during a virtual advisory board meeting held on 16 December, 2024, attended by the authors-psychiatrists from Italy, Germany, Spain, Ireland and Portugal-together with representatives from Neuraxpharm, who market desvenlafaxine. The available evidence suggests that desvenlafaxine offers early symptom relief, sustained efficacy across diverse major depressive disorder symptom clusters, and benefits for patients with anhedonia, fatigue, cognitive dysfunction and functional impairment. Its tolerability and safety profile, including a lower risk of weight gain and drug-drug interactions, contributes to its ease of use and improved adherence. Based on the authors' clinical consensus, desvenlafaxine may be particularly suitable for working-age adults, perimenopausal and menopausal women, those with general medical comorbidities or polypharmacy concerns, and individuals requiring an antidepressant with a broad mechanism of action. In addition, its predictable pharmacokinetics make it a practical choice in primary care settings. While most current guidelines typically recommend selective serotonin reuptake inhibitors as first-line treatment, the favourable tolerability profile and efficacy of desvenlafaxine across diverse symptom clusters may support its consideration as a first-line option in select patient populations. Depression is a common mental health condition that can seriously impact on a person’s daily life, work and relationships. Many people with depression struggle to find an effective treatment, and even when they do, side effects such as weight gain or sexual dysfunction can make it difficult to continue taking medication. Desvenlafaxine is a type of antidepressant known as a serotonin-noradrenaline reuptake inhibitor. It works by targeting two important chemical pathways in the brain—serotonin and noradrenaline—which help improve depressive symptoms. This article reviews the scientific evidence on how well desvenlafaxine works, how safe it is, and which patients may benefit most from it as a first-choice treatment for depression. This article is based on a review of the existing published literature and clinical insights from a meeting of psychiatry experts from different countries. The findings suggest that desvenlafaxine can provide relief from symptoms of depression early in treatment, is effective for patients with low energy, difficulty concentrating or lack of motivation, and is less likely than some other antidepressants to cause weight gain. Based on the available evidence and the experts’ experience, desvenlafaxine may be particularly useful for patients who take multiple medications as it has a lower risk of interactions with other drugs. While not suitable for everyone, desvenlafaxine may be a valuable option for many people with depression, particularly those who need quick symptom relief, actively employed adults, perimenopausal women, individuals with comorbid physical health conditions, and those who struggle with fatigue and cognitive problems.
Breast cancer stem cells (BCSCs) are a minor population within breast cancer tissue, causing cancer development and cancer recurrence due to stem-like and malignant properties, including self-renewal, proliferation, differentiation, migration, invasion, metastasis, and resistance to chemo/radio therapy. Treatment of these types of cancer cells requires targeted approaches to address the unique properties of BCSCs. Metal nanoparticles (MNPs) can be applied as drug delivery nanosystems in the treatment of BCSCs. Breast cancer treatments by MNP-based targeted drug delivery are essential because they reduce patient discomfort and recovery time, while enabling more precise and targeted therapy, potentially reducing off-target effects when appropriately designed and dosed. The size, shape, surface characteristics, and unique properties of MNPs, including their optical and physicochemical characteristics, safety profiles that are highly dependent on particle design and administration parameters, stability, circulation half-life, biodistribution, and high drug release efficiency, make them highly reactive and versatile for a variety of biomedical applications. However, their safety profiles are strongly influenced by particle design, dosage, and administration parameters, as high concentrations may induce dose-dependent toxicity, including ROS-mediated cellular damage. This review focuses on applications of various MNPs, including gold, copper, iron oxide, and silver, their surface modifications, and combination with photothermal therapy and several therapeutic agents in the drug delivery of BCSCs. This review also highlights the advantages, current challenges, and prospects of MNPs in drug delivery systems. These promising approaches have significant potential for developing new strategies for invasive treatment of breast cancer.
Glioblastoma (GBM) remains the most lethal primary brain tumor, with a median survival of 15 months and a 10-year survival rate of <1%. While current research into the dopaminergic system has largely focused on dopamine receptor antagonists, we aimed to investigate the potential therapeutic benefit of dopamine agonists (dopamine receptor D2) through the observation of incidental "super-survivors." We report two cases of adult GBM patients who received concurrent treatment with dopamine agonists for unrelated comorbidities. The first patient, treated with the ergot derivative bromocriptine for a prolactinoma, presented with multifocal disease and underwent subtotal resection. Despite developing a recurrence, he remains alive and progression-free for >11 years after diagnosis. The second patient, a 70-year-old male with Parkinson's disease treated with the non-ergot dopamine agonist pramipexole and with Sinemet, which increases the amount of available dopamine. He had a low Karnofsky Performance Score and received minimal adjuvant therapy. Despite these poor prognostic factors, he achieved a progression-free survival of 15 months and did not succumb to tumor progression. These observational cases suggest a hypothetical association between dopamine agonist therapy and improved survival outcomes in GBM, challenging the current paradigm that favors receptor antagonism. Given the safety, low cost, and blood-brain barrier penetrance of these Food and Drug Administration-approved drugs, we propose that dopamine agonists warrant further investigation as repurposed adjuvant agents in GBM treatment.
Androgenic alopecia (AGA) is a prevalent form of hair loss characterized by progressive miniaturization of hair follicles, significantly impacting patients' self-confidence and quality of life. Current FDA-approved treatments demonstrate limited to moderate efficacy. Microneedling combined with mesotherapy techniques has emerged as a promising drug delivery system for enhancing therapeutic outcomes in hair loss disorders. This retrospective interventional study aimed to evaluate the efficacy and safety of four distinct microneedling-based mesotherapy protocols for the treatment of androgenic alopecia. Sixty-three patients with clinically confirmed AGA were allocated to four treatment groups. All groups received microneedling therapy combined with different mesotherapy formulations: Group I (n = 16) received 2 mL hyaluronic acid (HA); Group II (n = 20) received 1.5 mL HA plus 0.5 mL finasteride; Group III (n = 15) received 1.5 mL HA plus 0.5 mL latanoprost; and Group IV (n = 12) received 1 mL HA plus 0.5 mL finasteride and 0.5 mL latanoprost. Patients underwent six treatment sessions at 3-4 week intervals. Standardized digital photographs were obtained at baseline, 3 months, and 6 months. Efficacy was assessed using physician satisfaction scores (treating and blinded evaluators) and patient satisfaction scores. Safety was monitored after each treatment session. Thirty-nine women and 24 men completed the study. Women demonstrated significantly higher improvement rates (48%) compared to men (29%). Female pattern hair loss showed better response (45%) than male pattern AGA (37.5%). Participants under 30 years achieved higher improvement rates (47%) compared to those aged 30-49 years (42.9%). Group IV (combination therapy with finasteride and latanoprost) demonstrated the highest efficacy across both sexes and hair loss patterns. All treatment protocols were well-tolerated with minimal adverse effects. The findings of the current study support the use of combination mesotherapy protocols for enhanced therapeutic outcomes in AGA management.
Current clinical guidelines recommend either muscarinic receptor antagonists or β3-adrenoceptor agonists for overactive bladder (OAB) treatment. These recommendations, however, are primarily based on short-term (12-week) clinical trials, leaving a critical gap in evidence regarding their long-term (≥1 year) efficacy and safety. Moreover, the long-term evidence synthesized here is limited to solifenacin and mirabegron, and its generalizability to other agents remains uncertain. To systematically compare the long-term efficacy and safety of solifenacin monotherapy, mirabegron monotherapy, and their combination in patients with OAB. We systematically searched PubMed, Embase, Cochrane Library, Scopus, and ClinicalTrials.gov for clinical studies published from inception to 2 April 2026. Two reviewers independently screened, selected, and extracted data. Methodological quality was assessed using the Jadad scale and the Cochrane Risk of Bias 2 (ROB 2) tool. The primary outcomes were changes from baseline in mean volume voided incontinence episodes per 24 h, and micturition frequency per 24 h. The secondary outcome was the incidence of treatment-related adverse drug reactions Quantitative meta-analysis was performed only for safety outcomes using a random-effects model. For the primary efficacy outcomes, substantial heterogeneity (I2>58%) across the included studies precluded meaningful pooling, therefore, a narrative synthesis of efficacy data was presented. Initial screening identified 7,451 articles, of which five randomized controlled trials met the inclusion criteria. For long-term OAB management, combination therapy (solifenacin 5 mg + mirabegron 50 mg) may be more effective than each monotherapy in improving MVV and reducing mean incontinence episodes and micturition frequency. Compared to mirabegron 50mg, solifenacin 5 mg was associated with a potentially higher risk of ADRs such as dry mouth (RR 1.73, 95%CI 0.91-3.30, P = 0.10) and constipation (RR 2.46, 95%CI 1.16-5.19, P = 0.02), but a lower incidence of dizziness (RR 0.08, 95%CI 0.01-0.62, P = 0.02). Solifenacin 5 mg was associated with a lower risk of constipation and dry mouth compared to solifenacin 10 mg. For long-term OAB pharmacotherapy with the specific regimens evaluated, mirabegron 50 mg appears to offer a favorable profile due to its comparable efficacy and lower incidence of certain treatment-limiting ADRs. However, these findings cannot be generalized to other muscarinic receptor antagonists or β3-adrenoceptor agonists. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251056532, identifier CRD420251056532.
The quantitative determination of drug purity is a critical aspect of pharmaceutical quality control, ensuring the safety, efficacy, and regulatory compliance of pharmaceutical products. Conventional analytical techniques such as high-performance liquid chromatography (HPLC) and gas chromatography (GC) provide excellent analytical performance but often require extensive sample preparation, longer analysis times, and substantial solvent consumption. Fourier Transform Infrared (FTIR) spectroscopy has emerged as a rapid, cost-effective, and environmentally friendly alternative for pharmaceutical analysis. This review critically evaluates recent advances in FTIR spectroscopy for the quantitative determination of drug purity in pharmaceutical dosage forms, with particular emphasis on sampling strategies, validation requirements, and chemometric applications. Published studies involving transmission FTIR, attenuated total reflectance (ATR-FTIR), and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) are systematically examined and compared. The role of chemometric techniques, including principal component analysis (PCA), partial least squares (PLS) regression, is discussed in overcoming spectral overlap and improving analytical performance. Validation parameters including linearity, accuracy, precision, specificity, limit of detection (LOD), and limit of quantification (LOQ) are critically assessed according to current regulatory guidelines. The reviewed studies demonstrate that FTIR spectroscopy, particularly when integrated with advanced chemometric methods, can provide reliable quantitative analysis of pharmaceutical compounds with analytical performance comparable to conventional techniques. Nevertheless, challenges related to model transferability, standardization, and regulatory acceptance remain. Future developments in machine learning-assisted spectroscopy, portable FTIR instrumentation, and harmonized validation protocols are expected to further expand the role of FTIR spectroscopy in pharmaceutical quality control and counterfeit drug detection.
Patients with spontaneous intracerebral hemorrhage (sICH) are at high risk for venous thromboembolism (VTE), a complication strongly associated with adverse clinical outcomes. While prophylactic anticoagulation has been shown to effectively reduce VTE incidence, significant uncertainty remains regarding its safety and the optimal timing of initiation. This article comprehensively reviews key aspects including anticoagulant selection, patient eligibility, therapeutic time windows, and current clinical challenges. Research gaps persist in defining appropriate anticoagulation strategies according to drug type, initiation timing, and sICH subtypes (e.g., lobar, deep, or amyloid-related hemorrhage). Future efforts should focus on conducting large-scale, multicenter, prospective clinical trials to validate the efficacy and safety of novel anticoagulants. Concurrently, integrating machine learning to develop high-precision risk prediction models, tailoring individualized treatment approaches, and establishing multidisciplinary collaborative research frameworks are essential steps toward advancing the standardization and rationalization of prophylactic anticoagulation in patients with severe sICH.
Schistosomiasis is a highly prevalent neglected tropical disease affecting more than 250 million people worldwide and currently relies on praziquantel (PZQ) as the only available treatment. This dependence raises concerns about the long-term sustainability of current control strategies and underscores the urgent need for new anthelmintic agents. In this context, natural products represent an important source of novel bioactive compounds. In the present study, the antischistosomal potential of sakuranetin (SAK), a flavanone isolated from Baccharis lateralis (Asteraceae), was evaluated. In silico analysis indicated favorable drug-like properties, including high predicted gastrointestinal absorption and absence of structural alerts. In vitro and in vivo safety assessments showed no cytotoxicity in Vero cells (CC50 > 500 μM) and no acute toxicity in Caenorhabditis elegans (LC50 > 1000 μM). When evaluated for direct antiparasitic effects, SAK did not exhibit detectable in vitro activity against adult Schistosoma mansoni worms. However, oral administration of SAK (400 mg/kg) in a S. mansoni murine model significantly reduced total worm burden by 84.4% and decreased fecal egg burden by 87.0% (PZQ: 88.2 and 95.9%, respectively). To support pharmacokinetic studies, a sensitive HPLC-UV method was validated (LLOQ = 50 ng/mL). SAK exhibited high plasma protein binding (unbound fraction = 8.3%) and was predominantly metabolized via glucuronidation in rat liver microsomes (t 1/2 = 149 min). These findings support SAK as a promising natural product-derived lead with significant in vivo antischistosomal activity and favorable drug-like properties.
Oral administration is favored for its safety, convenience, and cost-effectiveness, yet remains limited by the harsh gastrointestinal environment that often compromises drug stability and efficacy. Plant-derived extracellular vesicles (PDEVs) represent a promising natural platform to overcome this challenge. Exhibiting inherent anti-inflammatory, antioxidant, and anti-tumor properties, PDEVs demonstrate remarkable structural resilience under acidic and enzymatic conditions. Their capacities to cross intestinal barriers, deliver functional microRNAs, and encapsulate poorly bioavailable drugs have shown therapeutic potential in models of intestinal inflammation, metabolic disorders, and gastrointestinal cancers. This review systematically outlines the structural and functional characteristics of PDEVs and evaluates their emerging role as oral carriers for diverse cargoes, including small molecules, nucleic acids, proteins, and probiotics. We also discuss their advantages, design principles, recent advances, current limitations, and future perspectives.
Human epidermal growth factor receptor 2-targeted antibody-drug conjugates-ado-trastuzumab emtansine and trastuzumab deruxtecan-have transformed the treatment of human epidermal growth factor receptor 2-positive breast cancer. Because their antibody backbone derives from trastuzumab, which is associated with reversible left ventricular (LV) dysfunction, cardiovascular safety remains clinically relevant. In pivotal randomized trials, symptomatic heart failure was rare, and clinically significant declines in LV ejection fraction (LVEF) were uncommon: LV dysfunction occurred in roughly 0.4-1.8% of ado-trastuzumab emtansine-treated patients and approximately 2.7-4.6% of trastuzumab deruxtecan-treated patients, almost always asymptomatic and frequently reversible. However, these reassuring estimates derive from populations selected for normal baseline LVEF and limited cardiovascular comorbidity, with short follow-up and endpoints anchored to LVEF. Reliance on serial LVEF alone may underestimate cardiovascular injury, because LVEF is insensitive to early, subclinical dysfunction. Global longitudinal strain and cardiac biomarkers (troponins and natriuretic peptides) detect myocardial changes earlier and are endorsed by contemporary cardio-oncology guidelines, although prospective validation specific to antibody-drug conjugates is lacking, and strain-guided management has not improved long-term outcomes. We examine why LVEF-only surveillance is incomplete and outline a risk-stratified, multimodal monitoring framework grounded in current guidelines.
FDA approvals of gene therapies began slowly and were concentrated within a few early modalities, but recent years have seen a marked acceleration across RNA-based agents, viral and non-viral in vivo platforms, and ex vivo genetically modified cell therapies. This expansion reflects the maturation of gene therapy into a diverse therapeutic class while revealing scientific, regulatory, and economic challenges that traditional development paradigms cannot fully accommodate. In response, FDA has introduced platform-aligned, risk-based initiatives-including the plausible mechanism framework, CMC flexibility initiative, and advanced manufacturing technologies program-to support individualized, mechanistically targeted, and potentially curative products. Persistent issues such as high upfront costs, manufacturing complexity, and payer constraints underscore the need for sustainable development and access models. Mechanistic and model-informed drug development, increasingly supported by AI/ML-enabled analytics, is becoming central to dose selection, safety evaluation, and durability prediction. These scientific, regulatory, and clinical-pharmacology perspectives define the evolving landscape of FDA gene therapy approvals and outline future directions needed to ensure durable benefit, equitable access, and long-term safety as genetic medicines expand into broader patient populations.
Colorectal cancer (CRC) represents one of the most prevalent and lethal malignancies worldwide, with rapidly increasing global incidence and mortality. Current clinical therapies for CRC are severely compromised by tumor metastasis, intrinsic and acquired drug resistance, and unsatisfactory prognosis for advanced patients, highlighting an urgent demand for novel and effective therapeutic candidates. As privileged multifunctional scaffolds, indole hybrids integrate diverse pharmacophores to achieve simultaneous modulation of multiple CRC-associated oncogenic signaling pathways and mutant proteins, enabling them to overcome the limitations of traditional single-target drugs, reduce systemic toxicity, and optimize pharmacokinetic performance. This review comprehensively summarizes the research progress of novel indole hybrids for anti-CRC therapy reported since 2021, excluding indole-pyrimidine and indole-pyridine hybrids covered in previous studies. Notably, among all summarized subclasses, indole-chalcone/chromene, indole-hydroxamic acid/benzamide, and indole-azole hybrids, show the most prominent and promising therapeutic outcomes. These three dominant hybrid categories display potent antiproliferative activity against both drug-sensitive and drug-resistant CRC cell lines, exert robust in vivo tumor growth inhibition in xenograft models, and possess favorable safety profiles with low cytotoxicity to normal cells. We systematically elaborate their key structure-activity relationships, core anti-CRC molecular mechanisms, including cell cycle arrest, apoptosis induction, and targeted pathway regulation, as well as superior preclinical pharmacological characteristics. Furthermore, the current challenges and future research directions for indole hybrid-based anti-CRC drug development are discussed.
Methylene bis-benzotriazolyl tetramethylbutylphenol (MBBT) is a UV filter and UV absorber used in cosmetics. In this study, the acute toxicity, repeated dose toxicity, skin irritation, ocular irritation, skin sensitization, reproductive, and developmental toxicity, genotoxicity, carcinogenicity, toxicokinetics, and dermal absorption of MBBT were evaluated. The oral and dermal LD50s of non-nanoform MBBT in rats were 2 g/kg. The LC50 of nanoform MBBT in rats was 0.488 mg/L. Neither 20% nanoform MBBT nor 65% non-nanoform MBBT caused skin irritation. Moreover, 50% nanoform MBBT did not cause ocular irritation and 30% non-nanoform MBBT did not induce skin sensitization. In reproductive and developmental toxicity studies in rats, neither male nor pregnant female rats nor fetuses exhibited adverse effects after receiving up to 1000 mg/kg/day of non-nanoform MBBT. In vitro bacterial reverse mutation assays, micronucleus tests, and gene mutation assays, as well as in vivo micronucleus assays, yielded negative results. The NOAEL of MBBT was determined to be 1000 mg/kg/day (the highest dose tested) on the basis of the results of a 90-day repeated dermal toxicity study in rats. The NOAEL was optimized to the internal dose by applying a dermal absorption rate of 5.922%, resulting in a systemic point of departure (PODsys) for MBBT of 59.22 mg/kg/day. The systemic exposure dose was calculated to be 0.0136 mg/kg/day. The margin of safety of MBBT was calculated to be greater than 100 when used at a concentration of 10% as a UV filter in all cosmetic products, suggesting that its use as a cosmetic ingredient is safe under the current usage conditions.
Pharmaceutical research and development has accumulated vast and heterogeneous archives of data. Much of this knowledge stems from discontinued programs, and reusing these archives is invaluable for reverse translation. However, in practice, such reuse is often infeasible. In this work, we introduce DiscoVerse, a multi-agent co-scientist designed to support pharmaceutical research and development at Roche. Designed as a human-in-the-loop assistant, DiscoVerse enables domain-specific queries by delivering evidence-based answers: it retrieves relevant data, links across documents, summarizes key findings and preserves institutional memory. We assess DiscoVerse through expert evaluation of source-linked outputs. Our evaluation spans a selected subset of 180 molecules from Roche's research and development repositories, encompassing over 0.87 billion Byte-Pair Encoding (BPE) tokens and more than four decades of research. To our knowledge, this represents the first agentic framework to be systematically assessed on real pharmaceutical data for reverse translation, enabled by authorized access to confidential archives covering the full lifecycle of drug development. Our contributions include: role-specialized agent designs aligned with scientist workflows; human-in-the-loop support for reverse translation; expert evaluation; and a large-scale demonstration showing promising decision-making insights. In brief, across seven benchmark questions, DiscoVerse achieved near-perfect recall (≥0.99) with moderate precision (0.71 - 0.91). Qualitative assessments and three real-world pharmaceutical use cases further showed faithful, source-linked synthesis across preclinical and clinical evidence.