Basic & Clinical Pharmacology & Toxicology最新文献

Precision medicine has significantly advanced through the development of predictive biomarkers based on pharmacogenetic (PGx) testing. These tests identify interactions between drugs and genetic variants that influence patient responses to treatments. Understanding genetic variations in drug-metabolizing enzymes, receptors and transporters and their impact on pharmacokinetics and pharmacodynamics allows for the prediction of drug effects and side effects, enabling tailored treatments for different patient groups. This review focuses on drugs metabolized by cytochrome P450 (CYP450) enzymes, for example, citalopram and clopidogrel or transported by the solute carrier organic anion transporter family member 1B1 (SLCO1B1), for example, atorvastatin and simvastatin, with PGx dosing guidelines, in the context of consumption in Scandinavian countries. A major barrier to the widespread adoption of PGx tests in clinical practice has been healthcare professionals' uncertainty about their efficacy, complexity in result interpretation and questions regarding the evidence base. However, recent studies have demonstrated PGx testing has the potential to improve treatment outcomes, reduce adverse drug reactions and achieve cost savings. These findings underscore the potential of PGx testing as a valuable tool in clinical decision making, promoting its use in a pre-emptive manner to enhance patient care.

Male sexual dysfunction, characterised by reduced libido, ejaculatory issues and erectile dysfunction, often results from oxidative stress and enzymatic imbalance, notably involving phosphodiesterase type 5 (PDE5) and nitric oxide synthase (NOS). This study explores the therapeutic potential of β-caryophyllene (β-CBP), a sesquiterpene with antioxidant and anti-inflammatory properties, in mitigating paroxetine-induced sexual dysfunction in rats. Male Wistar rats were divided into nine treatment groups: control, paroxetine (20 mg/kg/day), sildenafil (20 mg/kg/day), β-CBP (10 mg/kg/day), β-CBP (20 mg/kg/day), paroxetine with β-CBP (10 mg/kg), paroxetine with β-CBP (20 mg/kg), paroxetine with sildenafil and β-CBP with sildenafil. Sexual behavioural assays were evaluated, along with oxidative stress markers, including superoxide dismutase (SOD) and catalase (CAT) activity in penile tissue, assessed using spectrophotometric analysis. CB2 receptor expression was significantly increased in β-CBP-treated groups, suggesting enhanced cannabinoid receptor-mediated signalling, which may be linked to improved erectile function. The effects were dose-dependent, with the 20 mg/kg β-CBP group displaying the most significant improvements. Additionally, β-CBP restored antioxidant enzyme activities, including SOD, CAT and reduced glutathione (GSH) levels in penile tissue, effectively reducing oxidative stress. β-CBP shows promise as a therapeutic agent for male sexual dysfunction by enhancing antioxidative capacity and modulating enzymatic balance.

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By 2050, roughly 60% of the population will have cardiovascular disease. While a substantial amount of data has been generated over the last few decades that has aided in our understanding of cardiovascular disease pathology, less is known about how to increase resiliency to cardiovascular risk factors that individuals are exposed to on a daily basis. The vascular endothelium is considered the first line of defence against circulating noxious stimuli and, when dysfunctional, is an early risk factor for the development of cardiovascular disease. A vast amount of data has been generated demonstrating how external stress impairs the vascular endothelium; however, there is a paucity of knowledge regarding how to amplify protective pathways and ward off stress and the development of disease, which is the focus of this review. Targeting known protective endothelial pathways may be feasible to increase resiliency to vascular stress. Leveraging stress to boost defence mechanisms within the vascular endothelium is also proposed and may help identify novel therapeutic targets to protect individuals from the stress of everyday life.

In the search for novel treatment strategies for alcohol use disorder (AUD), glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) approved for treating Type 2 diabetes and obesity have caught much attention. GLP-1 is a naturally occurring peptide produced in the small intestines and the brain, regulating plasma glucose levels and satiety. This focused review will report on the preclinical studies, case stories, register-based cohort studies, brain-imaging data and secondary analysis of clinical data supporting the role of GLP-1RAs as a novel treatment of AUD. Several clinical trials are ongoing, examining the potential effects of the GLP-1RA semaglutide in AUD.

Fluvoxamine (FLV), a selective serotonin reuptake inhibitor, is commonly used to treat anxiety, major depressive disorder and obsessive-compulsive disorder, among other psychiatric conditions. This study aims to evaluate the effectiveness of FLV in mitigating damage caused by lipopolysaccharide (LPS) to the female genital tract. Thirty-two female Wistar Albino rats were randomly divided into four groups: control, LPS, LPS-FLV and FLV. At the end of the experimental period, tissues from the ovaries, fallopian tubes and uterus were collected for histological, immunohistochemical and genetic analyses. Histological examination of the LPS group revealed mild to moderate bleeding, oedema and neutrophil infiltration. Additionally, there were signs of endometrial damage in the uterus and loss of cilia in the fallopian tubes. Immunohistochemical analysis showed that LPS increased the expressions of nuclear factor kappa beta (NF-κB) and cation-dependent mannose 6-phosphate receptors (CD-MPR) and reduced kisspeptin-1 (KISS-1) expression. Genetic analysis indicated that LPS increased the expression of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) and aquaporin4 (AQP4) genes while decreasing Claudin-1 expression. However, all these adverse effects were reversed by FLV treatment. The study's findings suggest that FLV may be beneficial in treating LPS-induced damage to the female reproductive system.

The pineal gland secretes melatonin, which regulates various physiological processes; damage to this gland disrupts these functions. This study aimed to investigate the effect of nonylphenol on the pineal gland and the pituitary–adrenal axis, which is associated with this system. The study was initiated using Wistar albino male rats on their postnatal 21st day, a critical developmental stage for endocrine regulation. Nonylphenol was administered via oral gavage at doses of 5, 25 and 125 mg/kg/day, while bisphenol-A was given at 50 mg/kg/day as a positive control. At the end of the treatment period, liver, kidney, pituitary, pineal and adrenal tissues were examined histopathologically. Hormone levels were analysed in serum samples. Significant changes in adrenocorticotropic hormone, melatonin and aldosterone levels were detected in hormone analyses. In contrast, no differences in corticosterone and glucose levels were detected. Histopathological findings showed structural changes in tissues. The effects of nonylphenol on the pituitary–adrenal axis and melatonin vary depending on the experimental protocols employed. However, it is clear that nonylphenol and bisphenol A have negative effects on the pituitary–adrenal axis, pineal gland, liver and kidney. In conclusion, future research should focus on elucidating the molecular mechanisms underlying these effects and developing environmentally friendly strategies to eliminate nonylphenol and bisphenol-A contamination.