Novel heterocyclic hybrids of Thiophene clubbed 1,3,4-oxadiazoles targeting dihydrofolate reductase (DHFR): An in silico approach, molecular docking, ADMET studies, MM-GBSA assay and MD simulations.

There is an increasing amount of evidence on microbiome-drug interactions in several clinical settings, including in immunocompromised patients. The gut microbiome has been shown to directly and indirectly influence drug efficacy and toxicity, offering high potential for clinical translation. This narrative review aims to provide an up-to-date overview of the relationship between gut microbes and drugs, with a focus on immunochemotherapy in immunocompromised hosts, including oncological and transplant patients. We searched PubMed to identify relevant literature in English up to February 2026, as well as included articles known to the authors (prioritizing clinical studies wherever possible). For commonly used anticancer drugs in untargeted conventional chemotherapy, gut microbes may directly activate prodrugs, inactivate biologically active drugs, and/or interfere with their toxicity. Furthermore, indirect mechanisms of immune system modulation have been shown to enhance or worsen therapeutic outcomes, including in targeted immunotherapy. For immunosuppressants in transplant recipients, there is less available evidence overall. Nevertheless, existing studies support the role of the gut microbiome in influencing pharmacokinetics, including enterohepatic recirculation, also through modulation of host drug-metabolizing enzymes. Notably, some studies have demonstrated the potential of targeted microbiome manipulation to improve therapeutic outcomes. However, most of this information derives from small, heterogeneous studies, including animal models and in vitro studies. The translational implications of microbiome research in pharmacology are of paramount importance. Well-designed clinical studies and the integration of in vivo and ex vivo models will be essential for advancing knowledge and providing mechanistic insights into microbiome-drug interactions. In parallel, advanced computational approaches such as artificial intelligence and machine learning tools will facilitate the analysis of complex microbiome data. These approaches will help identify clinically relevant microbial signatures, including high-risk microbiome-drug interactions. This will enable the development of personalized precision strategies to improve clinical outcomes and prolong disease-free survival.

The dual challenges of drug resistance and toxicity in cancer therapy necessitate the development of new drugs with high efficacy and safety. Selenopeptides, which synergistically combine selenium's redox regulation capabilities with the tumor-targeting specificity of peptides, represent a promising frontier in antitumor drug development. Based on the recent literature, this review summarizes the sources and preparation methods of selenium peptides, such as enzymatic hydrolysis and solid/liquid-phase synthesis. Furthermore, it elucidates their multitarget mechanisms of action, including the modulation of the PI3K/Akt signaling pathway, activation of immune cells, inhibition of angiogenesis, and induction of cancer cell apoptosis. Evidence from in vitro, in vivo and preliminary clinical studies confirms their effectiveness in inhibiting cancer cell proliferation and reducing tumor markers. This article reviews the current research progress to provide a comprehensive reference for the clinical translation and application of selenium peptides in cancer therapy.

Pancreatic cancer remains one of the most lethal malignancies due to low response to chemotherapy. Focused ultrasound (FUS) has emerged as a promising strategy for enhancing tumor-specific drug delivery. However, chemotherapy in combination with FUS has still been limited by the unique tumor environment of pancreatic cancer. Thus, FUS application to clinical trials has been sufficiently considerable by several side effect. Therefore, many preclinical and clinical trials have been conducted to accelerate clinical application. This study demonstrates the effects of FUS-induced mechanical and thermal energies on drug delivery efficiency and safety in a PANC-1 xenografted BALB/c mouse model. Reflected acoustic pressure from tumors were analyzed to quantify cavitation effects, and enhancement of drug delivery investigated by fluorescence imaging. Anti-tumor efficacy with FUS exposure was compared using FOLFIRINOX. H&E, TUNEL assay and serum biochemistry were evaluated for the comparison of toxicity. The results demonstrated that increase of cavitation dose was dominantly dependent on the intensity, not duty cycle inducing thermal effect for the enhancement of drug accumulation to tumor. Mechanical effects by 2.0kW/cm2-ISPPA and 1% duty cycle enhanced drug accumulation to tumor by 1.57-fold without tissue damage. Also, FOLFIRINOX combined with mechanical effects achieved superior antitumor efficacy, with 83.0% tumor inhibition compared to 48.0% with FOLFIRINOX alone. And mechanical effect was validated as a non-toxic energy for tumor treatment by H&E, TUNEL assay and serum biochemistry analysis. In conclusion, FUS-mediated mechanical effects can be one of candidate as a safe and effective strategy for tumor-specific drug delivery.

Protocol for the generation and xenotransplantation of human induced pluripotent stem cell-derived neural progenitor cells into the mouse forebrain.

Organoids in drug development: from predictive models to regulatory integration.

Temazepam has not been adequately investigated for its long-term safety profile in broad patient populations. This study aimed to characterize temazepam's real-world long-term safety profile. Reports of adverse events from Q1 2006 to Q4 2025 comprising temazepam were collected from the FAERS database. Data were analyzed using disproportionality methods including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the multi-item gamma poisson shrinker (MGPS), and the Bayesian confidence propagation neural network (BCPNN). A total of 2788 adverse event reports associated with temazepam were retrieved. The most frequently reported events were drug ineffective, eye irritation, and toxicity to various agents. We also detected numerous ocular risk signals absent from the product label, together with potential abuse signals. Furthermore, our study identified several behavioral risk signals such as abnormal behavior, aggression, and amnesia and parasomnias-related adverse events like nightmare and somnambulism. A comprehensive analysis of the large scale real world FAERS database was performed in this study identifying an extensive spectrum of adverse events associated with temazepam. Our study confirmed established risks and detected potential novel signals including ocular toxicities (e.g., eye irritation, intraocular pressure increased, glaucoma, eye inflammation, and photophobia) as well as neuro behavioral adverse outcomes such as aggression, amnesia and parasomnias (e.g., nightmare and somnambulism). These findings provide compelling support for temazepam clinical monitoring and risk assessment.

Although extensive studies have been conducted on cytochrome P450 (CYP) enzymes in rodents and humans, research on canine CYP enzymes is limited. The lack of species-specific metabolic research on dogs presents a major challenge in predicting toxicity and adverse drug reactions. This study aimed to examine the interspecies differences in CYP enzyme activity and mRNA expression between canine and human hepatocytes following treatment with acetaminophen (AAP), diclofenac (Dic), or valproic acid (VPA). We determined the 24-h exposure half-maximal inhibitory concentration (IC₅₀) values of AAP, Dic, and VPA in canine and human hepatocytes. Based on these IC₅₀ concentrations, we compared drug-induced alterations in various parameters, including immunocytochemistry, transcriptomic profiles (RNA-seq), and CYP activity, to assess changes at the gene and protein levels. AAP and VPA increased CYP2J2 mRNA expression by 4.7- and 7.76-fold, respectively, whereas Dic increased CYP1A1 mRNA expression by 14.25-fold in canine hepatocytes. AAP, VPA, and Dic decreased CYP26B1 mRNA expression in canine hepatocytes by 0.03-, 0.12-, and 0.17-fold, respectively. Dic and VPA increased CYP1A1 mRNA expression by 5.53- and 6.66-fold, respectively, whereas AAP, VPA, and Dic decreased CYP4F22 mRNA expression by 0.03-, 0.13-, and 0.13-fold, respectively, in human hepatocytes. The observed differences between species in CYP activity and mRNA levels in response to drug exposure highlight the importance of accurate and precise experimental models for the development of new medications.

Pharmacovigilance, the science of detecting, assessing, and preventing Adverse Drug Reactions (ADRs), is a critical component of safe healthcare practice. Although homoeopathic medicines are widely perceived as safe due to their high dilution, emerging evidence indicates that ADRs may occur because of factors such as improper preparation, contamination, incorrect prescribing, and the use of mother tinctures or low potencies. This paper explores the importance of pharmacovigilance in homoeopathy with a particular focus on phytochemistry, as many homoeopathic remedies are derived from plant sources containing biologically active compounds. The study highlights the need for systematic monitoring of ADRs to ensure patient safety, promote rational prescribing, and fulfil regulatory requirements. It discusses how phytochemical constituents—such as alkaloids, flavonoids, and essential oils may contribute to both therapeutic effects and potential adverse reactions, especially in lower dilutions where trace amounts of active substances remain. Common ADRs in homoeopathy, including initial aggravation, hypersensitivity reactions, toxicity, and possible drug interactions, are also examined. Furthermore, the paper emphasizes the role of pharmacovigilance practices such as adverse event reporting, post-marketing surveillance, phytochemical profiling, and practitioner education. Integrating phytochemical knowledge with pharmacovigilance systems can enhance understanding of remedy safety and improve clinical outcomes. Overall, strengthening pharmacovigilance in homoeopathy will support evidence-based practice, build public trust, and ensure its safe integration into modern healthcare systems.

Enhancing tumor immunotherapy: the role of ultrasound-mediated micro/nano-bubbles targeting the tumor microenvironment.

Advanced Electrochemical Biosensing to Detect Mitochondrial Cytochrome C and DNA for Cancer Diagnosis

Polypharmacy, the concurrent use of five or more medications, remains a critical driver of adverse drug events (ADEs), falls, and hospitalizations in geriatric care. This narrative review evaluates the clinical impact of nursing and pharmacist-led interventions in optimizing medication regimens and facilitating safe deprescribing. Synthesizing 10 landmark studies and international guidelines, we examine the synergy of interprofessional teams. Pharmacist-led comprehensive medication reviews, guided by the 2023 AGS Beers Criteria® and STOPP/START v3, significantly reduce potentially inappropriate prescribing. Simultaneously, nurse-led monitoring proves essential for identifying early clinical markers of drug toxicity during routine care. Beyond clinical protocols, addressing psychological barriers-specifically patient

Preliminary Clinical Trial of Senicapoc in Hereditary Xerocytosis due to heterozygous KCa3.1 missense variant V282M

Bone cancer and especially osteosarcoma is one disease that has proven to be a challenging therapeutic area because of poor prognosis, systemic drug toxicity, and limited response to conventional therapy. As an alternative method of treatment delivery, the localized drug delivery systems have come up promising with controlled release, lesser side effects and better therapeutic results. Hydroxyapatite (HAp), which is a calcium phosphate mineral that occurs naturally and demonstrates high biocompatibility as well as osteoconductivity, has attracted a lot of interest in bone tissue engineering and specific drug delivery. Nevertheless, there are inherent shortcomings of it such as brittle and low drug loading capacity (typically 2–10 wt%), which demand functionalization strategies. Coatings with polymers (PEG, chitosan, PLGA), inorganic ions (Zn, Ag, Sr), and carbon-based nanomaterials (graphene, CNTs) have been demonstrated to increase mechanical strength, drug encapsulation and release kinetics (enhancing loading efficiency up to 60–85 % and prolonging release over 7–30 days). Nanocomposites constructed by HAp through co-precipitation, sol-gel, and hydrothermal techniques have been shown to deliver anticancer agents including doxorubicin, cisplatin and methotrexate with control. Additional targeting techniques such as ligand-mediated delivery, pH/enzyme-responsive release, and bone-seeking agents such as bisphosphonates further enhance targeting. The results of preclinical in vitro and in vivo studies suggest encouraging cytotoxicity against cancer cells, biocompatibility (osteoblast viability often >90 %), and sustained drug delivery, but challenges to translational scalability, reproducibility and clinical validation exist. Smart stimuli-responsive carriers, theranostic integration and individualized medicine strategy should be investigated in the future, with functionalized HAp nanocomposites being the advanced option in the next generation of localized bone cancer therapy platforms.

Introduction: The (1,3)-β-D-glucan (BDG) assay is a screening tool often used in combination with risk assessments to limit overutilization of antifungals with up to 80% reduction in micafungin duration of therapy (DOT). This stewardship approach could decrease potential drug toxicities, development of resistance, and excess costs. As there is no established consensus on the ideal patient population for use or use in combination with a defined algorithm, this study assessed the impact a BDG algorithm has on micafungin DOT compared to standard of care (SOC). Methods: This retrospective, multisite, pre-post cohort study at a tertiary health system included non-neutropenic critically ill adults on empiric micafungin with risk factors for invasive candidiasis (IC). A BDG algorithm was utilized from 9/2024- 1/2025 and compared to SOC in the prior year for the primary outcome of micafungin DOT. Secondary outcomes included length of stay (LOS), mortality, 30-day readmissions, cost, and BDG performance. Statistical analyses included regression modeling, group comparisons, and correlation analyses. Results: A total of 318 patients were screened to include 110 patients. Baseline characteristics were similar, with a lower rate of IC in the SOC than in the algorithm group (1.8% vs. 7.3%). Overall, micafungin DOT was not different between groups [94.7 (45.0-146.3) vs 95.4 (49.2-206.4) hours; p = 0.84] but was significantly shorter when BDG resulted within 48 hours [53.0 (46.1-98.1) vs. 140.7 (72.8-226.6) hours; p = 0.014] or with algorithm compliance following negative results [47.6 (35.6-68.8) vs 95.4 (49.2-206.4) hours; p = 0.005]. The test had negative and positive predictive values of 96.6% and 11.5%, respectively, with dialysis patients most likely to correlate with false positives (phi = 0.40, 95% CI: 0.15–0.60, p = 0.002). Patients who were immunocompromised or underwent surgery had prolonged DOT. Other outcomes were not significant. Conclusions: A pharmacy-driven BDG algorithm did not significantly decrease micafungin DOT except with BDG results within 48 hours or with algorithm compliance following negative results. The BDG test may have less impact in immunocompromised, surgery, and dialysis patients. This highlights the need for research in anti-fungal stewardship to optimize patient outcomes.

Safer-Use Spaces are recognized as one of the most effective ways to reduce the harms associated with the opioid and toxic drug crisis. This study performed an analysis of a gender-specific safer-use space in Hamilton, Ontario, using the therapeutic landscapes conceptual framework. We conducted eight in-depth one-on-one interviews with staff at the site, asking what parts of the social, built, and symbolic environments encouraged people who use drugs to return to the site. The thematic analysis found that the practicality and safety offered by the site, the control and agency felt by the clientele, and the ways in which clientele find sanctuary and oasis were valued by the clients. The study concludes with remarks on the importance of creating gender-specific, accessible, and empowering harm-reducing services for people who use drugs.

ABSTRACTIntroductionWe are at a critical juncture for drug policy reform. Toxic drug supply is driving unprecedented deaths in North America, with countries calling for decriminalisation. Policy reform in Australia has occurred in some states (e.g., decriminalisation in the Australian Capital Territory), stalling in others (e.g., the second supervised injecting facility [SIF] in Victoria). The objectives of this paper are to present trends in attitudes to drug policy in Australia, 2001–2022/23 and media reporting of related policies, to explore how public opinion and media attention have changed over time.MethodsAnalysis of (i) National Drug Strategy Household Survey data on attitudes to drugs/drug policies; and (ii) Factiva for media reporting.ResultsIn 2022/23, Australians supported needle and syringe programs (67.8%), SIFs (58.3%), take home naloxone (60.9%) and drug checking services (64.4%). They opposed legalisation of methamphetamine (86.6%), heroin (85.6%), cocaine (78.2%) and ecstasy (75.8%), while a larger proportion supported cannabis legalisation (44.6%). Australians supported a health response to possession of drugs (57.3% for methamphetamine, 80.9% for cannabis) rather than a criminal response. Methamphetamine was increasingly reported as the drug of most concern (2.9%–42.5%), decreasing for heroin (44.9%–11.4%), 2001–2022/23. Methamphetamine media articles increased (272–2426); heroin decreased (2136–973), 2000–2023. Mentions increased for SIFs (spiking at 175, 2019) and decriminalisation/legalisation (spiking at 242, 2019).Discussion and ConclusionsSupport for harm reduction remains high and low for legalisation. Media focused on methamphetamine, SIFs and decriminalisation/legalisation. Despite opposition towards legalisation, most Australians favoured a health response to drug use.

Chrono-pharmacology (often used interchangeably with chronopharmacology) examines how biological rhythms—especially circadian (≈24-hour) timing—shape drug absorption, distribution, metabolism, excretion, efficacy, and toxicity. This review synthesises contemporary mechanisms linking circadian biology to pharmacokinetics and pharmacodynamics, describes methodological principles for translating circadian insights into clinical dosing strategies, and evaluates evidence across therapeutic domains with an emphasis on cardiovascular, inflammatory, and oncologic applications. Over the last two decades, advances in molecular chronobiology have clarified that circadian clocks operate not only in the suprachiasmatic nucleus (the central pacemaker) but also in peripheral tissues such as the liver, gut, heart, immune cells, and tumours. These clocks orchestrate rhythmic transcriptional and post-translational programs that create predictable time-of-day variation in drug-processing proteins, target availability, pathway sensitivity, and repair mechanisms. Consequently, “when” a drug is taken can become as clinically meaningful as “which” drug is chosen, particularly for therapies with narrow therapeutic indices or time-sensitive targets. Finally, it outlines emerging technologies enabling individualised chronotherapy, including wearable-derived phase markers, digital phenotyping of sleep–wake behavior, and systems approaches that integrate multi-omics with pharmacology. Chrono-pharmacology reframes therapeutics as a time-aware intervention and offers a pragmatic path to optimise benefit–risk profiles without necessarily changing drug molecules—by aligning dosing with biology.

Background:Fentanyl has driven overdoses across the U.S. in heterogeneous ways, with local variation in non-fatal overdoses remaining under-described. We sought to estimate the contributions of fentanyl to non-fatal overdose among people who inject drugs (PWID) in San Diego, CA, during a period of substantial drug supply evolution.Methods:Using convenience sampling, we recruited PWID living in San Diego into a longitudinal cohort study involving biannual assessments of opioid use and non-fatal overdose from 10/2020–05/2024. Multivariable Poisson regression assessed longitudinal associations between past six-month fentanyl use and non-fatal overdose risk. We calculated the confounder-adjusted longitudinal population attributable fraction (LPAF) to quantify fentanyl’s contribution to non-fatal overdoses over time.Results:Among 204 participants, the median age was 40.5 years, 73.0% were male, and 68.1% experienced homelessness. Fentanyl use increased from 51.0%(104/204) at Visit 1(10/2020–10/2021) to 62.4%(68/109) at Visit 6(10/2023–05/2024) while non-fentanyl opioid use decreased from 39.7%(81/204) to 5.5%(6/109). Past six-month non-fatal overdose decreased from 22.5%(46/204) to 15.6%(17/109) overall, and from 38.5%(40/104) to 19.1%(13/68) among those using fentanyl. Significant associations between fentanyl use and non-fatal overdose risk were observed at Visits 1 (Adjusted Relative Risk (ARR) 5.97, 95%CI: 2.37–15.00) and 5 (ARR 4.19, 95%CI: 1.17–15.00). The percentage of non-fatal overdoses contributed by fentanyl use in this cohort (LPAF) was 35%(0.35, 95%CI: 0.17–0.52).Conclusion:The contribution of fentanyl to non-fatal overdoses varied over time in our cohort. Disentangling the role of contextual factors such as opioid tolerance, fentanyl potency, and behavioral changes will support intervention design amid increasingly toxic drug supplies.

Drug metabolism and toxicity are significantly influenced by the human gut microbiota. Recent research has brought attention to the possible influence of gut microbiota on drug safety and efficacy, underscoring the need for a deeper comprehension of the relationship between gut microbiota and drug metabolism. This review examines the intricate relationship between medication metabolism and the human gut microbiome. It talks about the many kinds of microbes that live in the human gut and the mutualistic relationship that exists between the gut microbiota and the human host. The paper also outlines the different ways that gut microorganisms might alter drug metabolism, as well as how drugs absorb and are bioavailable. It also talks about how understanding microbiota variances might lead to tailored therapy and gives examples of medications whose efficacy is affected by microbiome interactions. It also lists metabolic pathways that the gut microbiota affects and provides noteworthy instances of how the gut microbiota and drugs interact. In conclusion, it tackles issues like diversity in microbiota composition and clinical translation and potentially beneficial therapeutic techniques that take use of microbiota-drug interactions. The review wraps up by discussing about gut microbiota, concept of gut microbiota, drug metabolism by gut microbiota, stressing the significance of investigating the relationship between drug metabolism and gut microbiota and how it can affect healthcare.