Basic & Clinical Pharmacology & Toxicology最新文献

Aripiprazole, a third-generation antidepressant/antipsychotic drug, acts on serotonergic and dopaminergic receptors and is widely prescribed for mental disorders, such as depression and schizophrenia. Studies indicate that this class of drugs can impact directly on sperm quality and fertility. Then, this study evaluated the effects of subchronic exposure to aripiprazole on sperm quality and fertility of adult male Wistar rats. Thirty-six rats were divided into three groups: control, 3 mg/kg and 6 mg/kg of aripiprazole orally exposed for 28 days. Our results showed that aripiprazole significantly increased seminal vesicle weight at a dose of 6 mg/kg. Progressive sperm motility was reduced, and there was an increase in the diameter of the seminiferous tubules at a dose of 3 mg/kg. Fertility test was reduced at a dose of 6 mg/kg. These findings suggest that although aripiprazole is effective in treating mental disorders, it may have subtle adverse effects on reproduction, especially on sperm quality and fertility, raising concerns about its indiscriminate use at doses higher than those tested.

Neuroblastoma (NB), a neural crest-derived tumour, is one of the most common extracranial solid malignancies in children. Most patients are under 5 years old at diagnosis (median, 18 months) [1]. The main cause of death is metastasis with high-risk patients having a survival rate below 50% over 5 years. The main treatment for high-risk cases is multimodal involving surgery, chemotherapy, radiotherapy, immunotherapy and stem cell transplantation. However, despite aggressive therapy, more than 50% of children with high-risk NB relapse. Consequently, there is significant unmet need in diagnosing metastatic NB early and treating it effectively and, ideally, non-toxically [1].

Here, we aimed to elucidate the potential anti-invasive role of tetracaine. Tetracaine is a well-established blocker of voltage-gated sodium channel (VGSC) activity shown previously to promote metastatic cell behaviours in several cancers [2, 3]. It is in routine clinical use as a long-acting local anaesthetic [4]. Several human NB cell lines have been shown to express VGSCs [5, 6]. Indeed, a novel developmentally regulated (‘neonatal’) splice variant of Nav1.5 was first described in a NB cell line [5]. However, little is known about the possible pathophysiological role of VGSC expression in NB.

The study adhered to the Basic and Clinical Pharmacology and Toxicology policy for experimental and clinical studies [7]. All the procedures used, except the following, have been described already [2].

Six different human NB cell lines were adopted: SH-EP, IMR-5, SH-SY5Y, KELLY, SK-N-BE and SK-N-SH.

Tetracaine has anti-invasive effects on NB cells and, accordingly, may ultimately be repurposed as a safe clinical agent against NB especially its aggressive forms.

This study was supported by Pro Cancer Research Fund (PCRF).

M.B.A.D. holds shares in Celex Oncology Innovations Ltd., which aims to develop ion channel modulators as cancer drugs. The other authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Mycophenolic acid (MPA) is a widely used immunosuppressant whose use is often limited by gastrointestinal toxicity. Gut bacterial hydrolysis of liver-derived MPA glucuronides increases local exposure to MPA, potentially impairing epithelial barrier function and cellular metabolism. To explore the effects of MPA on gut barrier integrity and metabolic pathways in gut epithelial cells, Caco-2 cells were exposed to MPA (10 or 100 μM), and barrier function was assessed by transepithelial electrical resistance (TEER) and lucifer yellow (LY) permeability in both differentiated and early-stage monolayers, while intracellular metabolic changes were investigated using targeted LC–MS/MS metabolomics. In differentiated monolayers, MPA did not significantly alter LY transport or TEER measurements. In contrast, MPA exposure during the early stages of monolayer formation reduced TEER values, 3 days after MPA withdrawal (Day 6; p < 0.01). The effects of 100-μM MPA were still noticeable at Day 10, as confirmed by LY permeability (p < 0.05). Metabolomic profiling clearly separated exposed from control cells (PCA, PC1 + PC2 = 92% variance). At 10 and 100 μM, 9 and 8 metabolites were significantly altered, with 6 common to both doses. Pathway enrichment revealed perturbations mainly in nucleotide synthesis, consistent with altered metabolic activity.

Machine learning (ML)–based methods have been proposed as a potential approach for identifying candidate drugs to be repurposed as disease-modifying treatments for Parkinson's disease (PD). We applied an ML-based signal detection method to identify drugs associated with PD and evaluated the method's generalizability. An algorithm combining subsampling and lasso logistic regression was implemented in a case–control study of 12 257 PD cases and 81 103 matched controls identified in Finnish registers. Drug exposure was defined at the subgroup and drug substance levels of the Anatomical Therapeutic Chemical (ATC) classification, considering the frequency of dispensation over 2 years, starting 10 years before the index date (8-year lag). Three subgroups and two individual drugs were associated with reduced PD risk. Inhalant anticholinergics, in particular tiotropium bromide, showed the most robust signal. Other signals included antimalarial drugs (aminoquinolines) and the antibiotic subgroup lincosamides. Several drugs were associated with increased PD risk, as expected. In addition to direct pharmacological effects, observed associations could be due to treatment of prodromal symptoms of PD, increased comorbidity in individuals later diagnosed with PD or a combination of these factors. These results support the feasibility of the approach. Associations of decreased PD risk observed should be further investigated in view of drug repurposing.

Current antiseizure therapy for epilepsy is only effective in about 70% of the patient population. Previous studies had shown that the addition of small amounts of tetrahydrocannabinol (THC) made cannabidiol (CBD) much more potent in the maximal electroshock seizure (MES) model. The psychotoxic effects of THC make it unsuitable as an antiseizure therapy. The current study investigated the effects of combining CBD with the non-psychotoxic cannabinoid cannabigerol (CBG) in the MES model in mice. Mice were administered (i.p.) CBD or CBG or a combination of both before undergoing the MES procedure. Dose–response and dose–toxicity curves were generated for each compound and combinations. It was found that CBG has antiseizure properties and that it potentiates the effects of CBD. By using a 1:1 ratio combination of CBD and CBG, the ED₅₀ for CBD was reduced by over 50% and the TD₅₀ for CBD was reduced by 40%, indicating increased toxicity. This suggests that the interaction between CBD and CBG may be additive in nature. Both drugs showed little toxicity at therapeutic doses. This is the first study to provide detailed dose–response data for CBG as well as CBG in combination with CBD in a seizure model and suggests that the two drugs could act in a similar manner to suppress seizures.

Climate change poses a significant challenge for global health. The World Health Organization estimates 250 000 additional annual deaths between 2030 and 2050 due to global warming. The healthcare sector is a major contributor to greenhouse gas (GHG) emissions, accounting for approximately 4.4%–5.5% of a country's total carbon footprint, with medicines contributing 5%–10%. This scoping review provides an overview of existing literature on the climate impact of medicines in the hospital sector and identifies knowledge gaps. The review followed PRISMA-ScR guidelines, conducting a comprehensive literature search in PubMed and Embase. Peer-reviewed articles published in the last 20 years, reporting original data on GHG emissions from medicines in the hospital sector were included. Articles were categorized based on therapeutic area, enabling a structured mapping of current areas of evidence. Of the 2986 studies identified, 32 were included. Most focused on emissions from inhaled anaesthetic gases (n = 15), followed by inhaler therapies (n = 6), total healthcare systems (n = 4), ophthalmology (n = 3), surgical procedures (n = 2) and other areas (n = 2). The findings show that research on the climate impact of medicines in the hospital sector remains limited. Knowledge gaps persist across most therapeutic areas, highlighting the need for research to inform climate-friendly strategies and support decision-making.