Basic & Clinical Pharmacology & Toxicology最新文献

Ulcerative colitis (UC) is an inflammatory bowel disease and psychological factors may be one of its pathogeneses. Selective serotonin reuptake inhibitor drug such as paroxetine with an effective anti-depression ability may be a new option for UC treatment. To evaluate the therapeutic effect of paroxetine on the exacerbation of UC symptoms caused by depression, a dual model of C57BL/6 mice was established using dextran sulphate sodium and chronic unpredictable mild stress (CUMS). Behavioural experiments, H&E staining and the level of 5-hydroxytryptamine (5-HT) in the brain were used to demonstrate successful replication of the CUMS model. The levels of 5-HT, TNF-α and IL-1β in the colon and the activity of MPO in the serum were determined by ELISA kits. The levels of some gut microbiota in the faeces were measured by qPCR and faecal differential metabolites were analysed by ¹H NMR. The results indicate that CUMS can exacerbate UC symptoms in mice by exacerbating inflammation, and UC+CUMS can disrupt gut microbiota and fatty acid metabolism. Paroxetine can improve the mental state of mice, reduce serum MPO activity, but increase TNF-α and IL-1β levels in the colon. In addition, paroxetine also can restore the intestinal flora of mice and improve intestinal absorption and metabolic function of amino acids and short-chain fatty acids.

Autophagy is a vital mechanism that eliminates large cytoplasmic components via lysosomal degradation to maintain cellular homeostasis. The role of autophagy in cancer treatment has been studied extensively. Autophagy primarily prevents tumour initiation by maintaining genomic stability and preventing cellular inflammation. However, autophagy also supports cancer cell survival and growth by providing essential nutrients for therapeutic resistance. Thus, autophagy has emerged as a promising strategy for overcoming resistance and enhancing anti-cancer therapy. Inhibiting autophagy significantly improves the sensitivity of lung, colorectal, breast, liver and prostate cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). This review investigates the intricate interplay between autophagy modulation and TRAIL-based therapy, specifically focussing on comparing the efficacy of late-stage autophagy inhibition versus early-stage inhibition in overcoming cancer resistance. We expose the distinctive advantages of late-stage autophagy inhibition by exploring the mechanisms underlying autophagy's impact on TRAIL sensitivity. Current preclinical and clinical investigations are inspected, showing the potential of targeting late-stage autophagy for sensitizing resistant cancer cells to TRAIL-induced apoptosis. This review emphasizes the significance of optimizing autophagy modulation to enhance TRAIL-mediated therapy and overcome the challenge of treatment resistance in cancer. We offer insights and recommendations for guiding the development of potential therapeutic strategies aimed at overcoming the challenges posed by treatment-resistant cancers.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments. Selective ligands that specifically stabilize the CaMKIIα central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA), confer neuroprotection after ischemic stroke in mice where CaMKIIα is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKIIα hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14 days with either HOCPCA or Ph-HTBA (7 days pre-treatment and 7 days of behavioural assessment). Both compounds were well-tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKIIα autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKIIα via the selective hub ligands used here is not a viable treatment strategy in AS.

The MDM2-p53 pathway plays a pivotal role in regulating cell cycle and apoptosis, with its dysfunction contributing to approximately 50% of human malignancies. MDM2, an E3 ubiquitin ligase, targets the tumour suppressor p53 for degradation, thereby promoting uncontrolled cell growth in cancers. Inhibiting the MDM2-p53 interaction represents a promising therapeutic strategy for reactivating p53’s tumour-suppressive functions. This study explored the potential of ibutamoren (IBU) as a novel inhibitor of MDM2. In silico analyses utilizing molecular modelling revealed that IBU has a low IC₅₀ for MDM2 inhibition and favourably binds to the p53-binding pocket of MDM2. In vitro experiments demonstrated that IBU treatment reduced the viability of immortalized cancer cell lines with a functional MDM2-p53 pathway but not in cell lines where this pathway harboured damaging mutations. This trend was further supported by RT-qPCR analysis, which showed differential expression of two p53 target genes upon IBU treatment in cell lines with wild MDM2-p53 pathways but not in those harbouring damaging mutations. These findings provide preliminary evidence supporting IBU's anticancer activity, plausibly through the MDM2-p53 pathway, and suggest that further studies are warranted to explore its mechanism of action and potential development as a lead compound in oncology research.

Natural products constitute a vast source of bioactive compounds with the potential of providing valuable insight for future medicines. However, from a pharmacological perspective, natural product studies are also often accompanied by serious limitations due to, for example, the complex nature of biological extracts, the challenge of reproducibly characterizing the extract and providing an exhaustive list of constituents and, consequently, the difficulties in linking the observed pharmacological effects to specific chemical entities. The present paper discusses the major challenges of studies with natural products and provides a guideline to be followed by authors submitting research findings involving data from natural products, and their derivatives, to Basic & Clinical Pharmacology & Toxicology.

Daptomycin, an anti-methicillin-resistant Staphylococcus aureus drug, causes exposure-dependent muscle toxicity and eosinophilic pneumonia. Although the area under the concentration-time curve (AUC)-guided dosing is crucial, an optimal blood sampling strategy is lacking. This study aimed to identify an optimal limited sampling strategy using Bayesian forecasting to rapidly achieve the target AUC. Two validated population pharmacokinetic models generated a virtual population of 1000 individuals (models 1 and 2 represent diverse patients and kidney transplant recipients, respectively). The AUC for each blood sample was assessed using the probability of achieving the estimated/reference AUC ratio on the second day (AUC_24–48) and at the steady state (AUC_ss). In Model 1, Bayesian posterior probabilities for AUC_24–48 increased from 50.7% (a priori) to 59.4% and for AUC_ss from 48.9% (a priori) to 61.9%, with one-point C_trough sampling at 24 h. With two-point sampling at 7 and 24 h, the probabilities increased to 73.8% for AUC_24–48 and 69.7% for AUC_ss. In Model 2, the probabilities for both AUC_24–48 and AUC_ss with one-point C_trough or two-point sampling incorporating C_trough sampling increased compared to a priori probabilities. These results suggest that two-point sampling incorporating C_trough during initial dosing enhanced achieving the target AUC_24–48 and AUC_ss rapidly.

Although diloxanide is a drug of choice for treating asymptomatic amoebiasis, its mechanism of action (MOA) remains unclear. This review aims to shed light on the current understanding of the effectiveness and MOA of diloxanide in treating amoebiasis . It involves analysis of articles, retrieved from PubMed, Google Scholar and EBSCOhost, on diloxanide and the treatment of Entamoeba histolytica infection. Diloxanide is used in an ester form, which allows its high luminal concentration and greater efficacy than metronidazole in the management of asymptomatic amoebiasis. The current understanding of the action of diloxanide is based on its structural similarity to chloramphenicol at dichloroacetamide group. It acts against protein synthesis in E. histolytica trophozoites, blocking their conversion to more virulent and invasive cyst forms. Furthermore, it has a parasite clearance rate of 81–96% and treats amoebic abscesses when combined with metronidazole and chloroquine. Nevertheless, it is associated with adverse events such as flatulence, anorexia, headache and urticaria. Diloxanide is efficacious against amoebiasis but there is a need to explore its structure–activity relationship.The study suggests future directions, including novel drug formulations, diagnostic improvements, and combination regimens to enhance treatment outcomes and mitigate relapse associated with the use of diloxanide.

With increasing medicine use, more medicines are being stored at home, yet the understanding of household medicines remains limited. This study aimed to assess the amount, type and storage practices of medicines in households. It also explored the reasons for unnecessary or expired medicines, as well as the factors associated with the presence of expired medicines in a household. The online survey was conducted among loyal customers of University Pharmacy in June 2023 (n = 5004). The data were analysed for frequencies and percentages, and binary logistic regression was used to examine the association between background factors and expired medicines in households. On average, one household had 13.9 active, 2.8 unnecessary and 2.2 expired medicine packs. Medicines were typically stored in the kitchen (67.0%) and in cabinets (58.7%), and 40% were to be stored safely. The main reasons for unnecessary or expired medicines were improved health (39.2%), medication changes (31.9%) and oversized packs (28.0%). Households returning medicines biennially (odds ratio (OR): 2.85; 95% confidence interval (CI): 2.13–3.82) and those with many active medicines (OR: 2.14; 95% CI: 1.79–2.54) had expired medicines more often. The study showed that households had many medicines, highlighting the need for better storage and optimized packaging to improve safety, reduce waste and enhance rational pharmacotherapy.