Basic & Clinical Pharmacology & Toxicology最新文献

Infertility, defined as the failure to conceive after 1 year of regular unprotected intercourse, is increasingly prevalent and affecting younger populations. Traditional Chinese medicine (TCM) offers significant therapeutic potential for infertility, with its holistic approach and emphasis on syndrome differentiation minimizing the drawbacks of conventional hormone-based treatments. This review aims to summarize the regulatory mechanisms of infertility and evaluate the therapeutic effects of TCM, including single herbs and herbal formulas, along with their underlying mechanisms. Evidence suggests that TCM may contribute to the regulation of reproductive function through modulation of the hypothalamic–pituitary–ovarian axis, improvement of the local reproductive microenvironment and immune regulation. At the molecular level, studies have reported that bioactive components of certain TCM herbs interact with hormone receptors, cytokines' signalling pathways and antioxidant enzymes, thereby potentially influencing ovarian reserve, follicular development, endometrial repair and immune tolerance. This review highlights the theoretical basis for TCM in treating infertility and suggests that further mechanistic and clinical studies are essential to promote its clinical application and offer new, improved options for patients.

Asthma is a serious global health issue that affects millions of people worldwide. It is a heterogeneous disease characterized by inflammation, bronchial hyperresponsiveness and airway remodelling. Compounds from the coumarin class have been extensively documented in the literature as promising agents for asthma treatment. This review highlights the potential of coumarins and their effects in animal models of asthma. Articles from the past 10 years (2014–2024) were selected according to the guidelines of the PRISMA from the PubMed, Virtual Health Library (BVS) and ScienceDirect databases. The search strategy utilized descriptors from the Medical Subject Headings (MeSH) and Descriptors in Health Sciences (DeCS) databases. Were selected 18 articles after applying the inclusion criteria: full-text articles published in English and Portuguese, freely accessible and investigating coumarins and their derivatives with antiasthmatic activity. The coumarins most explored by the authors were imperatorin and osthole, and the results showed that these coumarins relax airway smooth muscle, reduce inflammation and the release of Th2 cytokines IL-4, IL-5 and IL-13 and increase protection against inflammation through pro-inflammatory cells, Th1, macrophages and dendritic cells. Thus, it is concluded that coumarins and their effects, particularly imperatorin and osthole, present a promising potential in asthma management and could serve as important molecular scaffolds for future investigations.

Oral nitrite supplementation enhances nitric oxide (NO) bioavailability and lowers blood pressure. Quercetin may facilitate the reduction of nitrite to NO. However, the combined effects of nitrite and Quercetin on gastric NO formation and blood pressure have not been explored. We investigated whether oral treatment with Quercetin enhances the gastric conversion of nitrite to NO (in vitro and in vivo) and exerts antioxidant and antihypertensive effects. Spontaneously hypertensive rats (SHR) were divided into six groups (n = 6/group): three groups treated with Quercetin 10 mg/kg followed 15 min later by water, nitrite 1 mg/kg (nonantihypertensive) or 15 mg/kg (antihypertensive) by gavage, and three similar control groups treated with vehicle, followed by the same nitrite treatments. Blood pressure, gastric NO, plasma nitrite, nitrate, nitrosylated species (RxNO) and aortic S-nitrosylated proteins were measured. Oxidative stress was also assessed. Quercetin treatment converted a nonantihypertensive dose of nitrite into an effective antihypertensive intervention in association with increased in vitro and in vivo gastric NO formation. However, Quercetin did not enhance nitrite-induced increases in systemic or vascular nitrite, nitrate, RxNO concentrations nor vascular protein nitrosation. Our results show that Quercetin is a potent enhancer of gastric NO formation from nitrite and amplifies its antihypertensive effects. This combination of drugs may represent a safe and effective therapeutic strategy.

Organophosphates have been used for decades as pesticides, insecticides and herbicides, both in agricultural and industrial settings. However, their toxic effects on multiple body systems limit their safety. The clinical presentation of organophosphate toxicity varies depending on the route and duration of exposure. Although most research is focused on their cholinergic toxicity, emerging evidence points to their crucial contribution to metabolic dysfunction, including Type 2 diabetes and neuroinflammation. Beyond acetylcholinesterase inhibition, recent research highlights the potential role of organophosphates in disrupting endocannabinoid signalling, particularly by affecting endogenous ligands that modulate G protein–coupled receptors. This dysregulation may contribute to organophosphate-induced metabolic disturbances and inflammation. This review aims to explore how chronic subtoxic exposure to organophosphates contributes to metabolic syndrome and neuroinflammation through disruption of insulin and endocannabinoid signalling. It highlights the role of the endocannabinoid system in mediating these effects and evaluates its potential as a therapeutic target in organophosphate-induced toxicity.

We aimed to quantify inter- and intra-patient variability in serum perampanel concentrations and assess whether concentrations predict efficacy or tolerability. We conducted a retrospective cohort study of 68 children and adolescents (< 18 years) treated at the Danish Epilepsy Centre (2017–2024), analysing 311 TDM samples. Dose-normalized concentration ratio was summarized as the concentration-to-dose-per-kilogram ratio (C:(D/kg)) and evaluated by age group and co-medication category: enzyme-inducing anti-seizure medications (ASMs), valproate or non-inducing ASMs. Clinical outcomes were change in seizure burden, seizure freedom and adverse effects. Perampanel concentrations were outside the recommended therapeutic range in 13.8% of samples, and C:(D/kg) varied 59.2-fold across patients. Children < 6 years had lower concentration than adolescents > 12 years, and enzyme-inducing ASMs markedly reduced C:(D/kg). Overall, 80.9% of patients had reduced seizure burden, and 20.6% became seizure-free, but serum concentrations did not correlate with seizure freedom or adverse effects. TDM is valuable for detecting under- or over-dosing caused by age-related clearance changes or enzyme-inducing co-medications. While dose adjustments can be guided by serum concentrations, optimization should ultimately target clinical seizure reduction and tolerability.

Several publications have reported elevated clozapine concentrations in patients experiencing infections or inflammatory reactions. Proposed mechanisms include increased levels of pro-inflammatory cytokines that may inhibit clozapine metabolism and enhanced binding of clozapine to the acute phase protein alpha-1-acid glycoprotein (AGP). We collected serum samples sent to our routine laboratory over a 15-month period for the analysis of clozapine. In the 1106 eligible samples, we measured AGP and C-reactive protein (CRP) levels. By using a linear mixed effects regression model, we found a clear association between higher AGP and CRP levels and higher dose-adjusted clozapine concentrations. As an example, an increase in the CRP level from 5 to 60 mg/L or an increase in the AGP level from 0.5 to 1.5 g/L would be expected to cause a more than twofold increase in the clozapine concentration. Our findings support and extend previous case reports and studies, suggesting that increased AGP levels during inflammatory states may play a significant role in the rise of clozapine plasma concentrations observed during illness. We propose that in addition to the clozapine concentration, CRP levels and clinical signs of adverse effects and toxicity should be closely monitored in patients with infectious or inflammatory diseases.