Basic & Clinical Pharmacology & Toxicology最新文献

{"title":"Medication use among the oldest old in the Faroe Islands—A national cross-sectional study","authors":"Beinta Joensen,&nbsp;Sunrit Niklasdóttir,&nbsp;Niels Joensen,&nbsp;Kaare Christensen,&nbsp;Maria Skaalum Petersen","doi":"10.1111/bcpt.14012","DOIUrl":"10.1111/bcpt.14012","url":null,"abstract":"<p>Aging is often associated with an increasing number of comorbidities that warrant use of multiple drugs which increases the use of potentially inappropriate medications (PIMs), drug–drug interactions (DDIs) and drug-related problems (DRPs). The aim is to assess the prevalence of polypharmacy, PIMs, DDIs and DRPs among Faroese residents aged ≥90 years. In this population-based cross-sectional study, 494 individuals ≥90 years were invited and 298 (60%) participated. A pharmacist-led medication review was performed based on self-information, electronic patient journal and the Faroese Prescription Registry. The prevalence of polypharmacy was 74% with no sex-difference. Approximately 60% of participants used PIMs, primarily benzodiazepines and proton pump inhibitors, the latter being a frequently implicated medication in DRPs. Opioid use was low compared with other Nordic studies. DRPs were observed for 79% with discrepancies in the medication lists as the most common cause, and DDIs were identified for 47% of participants, mostly moderately clinically relevant DDIs. In conclusion, the medication use among the oldest old Faroese resembled that in other Nordic countries with a high prevalence of polypharmacy and use of PIMs, especially PPIs and benzodiazepines. However, no sex-difference was noted in medication use and the use of opioids was low.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"833-845"},"PeriodicalIF":3.1,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140666902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper: From enigma to therapeutic target for neurological disorder","authors":"Jayant Patwa,&nbsp;Swaran Jeet Singh Flora","doi":"10.1111/bcpt.14010","DOIUrl":"10.1111/bcpt.14010","url":null,"abstract":"<p>Neurological disorders (NDs) have a negative impact on the lives of individuals. There could be two explanations for this: unclear aetiology and lack of effective therapy. However, research in the past few years has revealed the role of bio-metals dyshomeostasis in NDs. The imbalance in copper (Cu) concentration may be one of the main causative factors in NDs. In this review, we have discussed the role of Cu in NDs, especially Alzheimer's disease (AD), including the molecular mechanisms involved in Cu-associated NDs like oxidative stress, neuroinflammation, and protein misfolding. We have also summarized the recent Cu-targeting approaches and highlighted the in vitro and in vivo studies recently being reported on the subject. Based on the earlier published reports, it could be speculated that the Cu targeting strategy might be an interesting and potential therapeutic approach for NDs. Various difficulties must be overcome to develop safe and efficient Cu-targeting medications for NDs.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"778-791"},"PeriodicalIF":3.1,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables","authors":"Khadija Mansour,&nbsp;Nadia Ben Fredj,&nbsp;Helmi Ammar,&nbsp;Haifa Ben Romdhane,&nbsp;Ahmed Mhalla,&nbsp;Amel Chaabane,&nbsp;Zohra Chadli,&nbsp;Karim Aouam","doi":"10.1111/bcpt.14009","DOIUrl":"10.1111/bcpt.14009","url":null,"abstract":"<p>Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"805-817"},"PeriodicalIF":3.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140587073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing myocardial cell protection with xanthine derivative KMUP-3 potentiates autophagy through the PI3K/Akt/eNOS axis","authors":"Shang-En Huang,&nbsp;Jong-Hau Hsu,&nbsp;Bo-Wen Shiau,&nbsp;Yi-Ching Liu,&nbsp;Bin-Nan Wu,&nbsp;Zen-Kong Dai,&nbsp;Chung-Pin Liu,&nbsp;Jwu-Lai Yeh","doi":"10.1111/bcpt.14007","DOIUrl":"10.1111/bcpt.14007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Autophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP-3) treatment coincides with enhanced autophagy while also providing cardio-protection, we investigated the hypothesis that KMUP-3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The pro-autophagic effect of KMUP-3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP-3 treatment on cardiotoxicity, we used antimycin A-induced cardiomyocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>As determined by transmission electron microscopy observation, KMUP-3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP-3 significantly increased the expressions of autophagy-related proteins, LC3 and Beclin-1, both in a time- and dose-dependent manner; moreover, the pro-autophagy and nitric oxide enhancement effects of KMUP-3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP-3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP-3-enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"818-832"},"PeriodicalIF":3.1,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of sex and hydration status on kappa opioid receptor-mediated diuresis in rats","authors":"Hasnain M. Lalji,&nbsp;Christopher P. Bailey,&nbsp;Stephen M. Husbands,&nbsp;Sarah J. Bailey","doi":"10.1111/bcpt.14008","DOIUrl":"10.1111/bcpt.14008","url":null,"abstract":"<p>Understanding the function of the kappa opioid receptor (KOP) is crucial for the development of novel therapeutic interventions that target KOP for the treatment of pain, stress-related disorders and other indications. Activation of KOP produces diuretic effects in rodents and man. Sex is a vital factor to consider when assessing drug response in pre-clinical and clinical studies. In this study, the diuretic effect of the KOP agonist, U50488 (1–10 mg/kg), was investigated in both adult female and male Wistar rats that were either normally hydrated or water-loaded. The KOP antagonist norbinaltorphimine (norBNI, 10 mg/kg) was administered 24 h prior to U50488 to confirm the involvement of KOP. U50488 elicited a significant diuretic response at doses ≥ 3 mg/kg in both female and male rats independent of hydration status. U50488 diuretic effects were inhibited by norBNI pre-administration. Water-loading reduced data variability for urine volume in males, but not in females, compared with normally hydrated rats. Sex differences were also evident in U50488 eliciting a significant increase in sodium and potassium ion excretion only in males. This may suggest different mechanisms of U50488 diuretic action in males where renal excretion mechanisms are directly affected more than in females.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"792-804"},"PeriodicalIF":3.1,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring promising minor natural phenolic compounds in neuroprotection-related preclinical models","authors":"Carlos Franciney Moreira Vasconcelos,&nbsp;Agnieszka Zofia Neugebauer,&nbsp;Ricardo Basto Souza","doi":"10.1111/bcpt.14006","DOIUrl":"10.1111/bcpt.14006","url":null,"abstract":"<p>Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterised by the progressive loss of specific neuronal cell populations due to multifactorial factors, including neurochemical and immunological disturbances. Consequently, patients can develop cognitive, motor and behavioural dysfunctions, which lead to impairments in their quality of life. Over the years, studies have reported on the neuroprotective properties inherent in phenolic compounds. Therefore, this review highlights the most recent scientific findings regarding phenolic compounds as promising neuroprotective molecules against neurodegenerative diseases.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 6","pages":"770-777"},"PeriodicalIF":3.1,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimetindene—Is the minimum toxic dose for children too strict?","authors":"Michal Čečrle,&nbsp;Daniela Pelclová,&nbsp;Navrátil Tomáš,&nbsp;Sergej Zacharov","doi":"10.1111/bcpt.14005","DOIUrl":"10.1111/bcpt.14005","url":null,"abstract":"<p>Dimetindene is a sedating antihistamine indicated for the symptomatic treatment of allergic conditions. Dimetindene is marketed among others under the trade name Fenistil (oral solution). Toxicity data are limited, and there is no consensus on the dose at which children require hospitalization. Objective is to determine the potentially toxic dose in children. Data in children with age up to 15 years were obtained from hospital discharge reports. Of 139 paediatric hospital discharge reports, 23 cases (16.5%) were excluded because of uncertain ingestion. In 116 children (46 boys and 70 girls, mean age 2 years and 9 months ± 1 year and 1 month), the majority of children developed no symptoms (87 children, 75%, mean age 3 years±1 year) and the remaining 29 children (25%, mean age 2 years and 11 months ± 1 year and 3 months) developed only mild and spontaneously resolving symptoms of poisoning after a dose of 0.82 ± 0.32 mg/kg b.w. (range 0.26–1.82 mg/kg). In 98% of all cases, hospitalized children were observed for a maximum 24 h, and their condition did not require specific treatment. In conclusion, the prognosis for accidental dimetindene poisoning in children appears to be good and the minimum toxic dose has been determined to be 0.5 mg/kg b.w.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"750-755"},"PeriodicalIF":3.1,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics of oxcarbazepine active metabolite in Chinese paediatric patients with epilepsy: Model-based dose optimization","authors":"Wei Wu,&nbsp;Wen-sheng Yang,&nbsp;Xiao-yong Xu,&nbsp;Xi-lin Ge,&nbsp;Jinmiao Lu,&nbsp;Guang-fei Wang,&nbsp;Yi Wang,&nbsp;Zhi-ping Li","doi":"10.1111/bcpt.14000","DOIUrl":"10.1111/bcpt.14000","url":null,"abstract":"<p>The pharmacological activity of oxcarbazepine (OXC) is primarily exerted through its active 10-monohydroxy metabolite (MHD). Nonetheless, there is limited pharmacokinetic information available regarding paediatric patients with epilepsy treated with OXC, especially in infants and toddlers. Concurrently, this drug exhibits substantial variability in pharmacokinetics and therapeutic response across different individuals. We aimed to develop a model to quantitatively investigate factors that affect MHD pharmacokinetics to formulate a dosage guideline for OXC in Chinese paediatric patients. A total of 297 MHD trough concentrations were obtained from 287 epileptic children. Six body weight (BW)-based allometric models were used for population pharmacokinetic modelling, while investigating the impact of other covariates on the apparent clearance. The one-compartment model and age cut-off model for the apparent clearance (CL/F) were established to describe the pharmacokinetics of MHD. The probability to obtain target trough concentration ranges (TTCRs) of MHD between 3 and 35 mg/L was determined by Monte Carlo simulations for doses ranging from 8 to 90 mg/kg/day. A new dose optimization strategy combining the dosage guidelines and Bayesian method provides a tailored approach for Chinese paediatric epileptic patients based on their individual BW and desired TTCRs of MHD, and also supports current dose recommendations, with the exception of children weighing ≤5 kg.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"712-726"},"PeriodicalIF":3.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic–pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation","authors":"Ida Klitzing Storgaard,&nbsp;Elisabeth Kjær Jensen,&nbsp;Søren Bøgevig,&nbsp;Torben Balchen,&nbsp;Anders Holten Springborg,&nbsp;Mike Allan Royal,&nbsp;Kirsten Møller,&nbsp;Mads Utke Werner,&nbsp;Trine Meldgaard Lund","doi":"10.1111/bcpt.14004","DOIUrl":"10.1111/bcpt.14004","url":null,"abstract":"<p>The objective of this study was to develop a population pharmacokinetic–pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic–pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic–pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"676-685"},"PeriodicalIF":3.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140172870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-molecule inhibitor HI-TOPK-032 improves NK-92MI cell infiltration into ovarian tumours","authors":"Mengqi Deng,&nbsp;Ruiye Yang,&nbsp;Qi Sun,&nbsp;Jiamin Zhang,&nbsp;Jinwei Miao","doi":"10.1111/bcpt.14002","DOIUrl":"10.1111/bcpt.14002","url":null,"abstract":"<p>The effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin-2 (IL-2). Genetically modified NK-92MI cells, which can release IL-2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL-2 administration. The role of PSD-95/discs large/ZO-1 (PDZ)-binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK-92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small-molecule inhibitor HI-TOPK-032, which inhibits PBK, enhances the cytotoxicity of NK-92MI cells toward OV cells. It increases the production of interferon-γ and tumour necrosis factor-α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI-TOPK-032 upregulates CD107a on NK-92 cells. In vivo studies demonstrated that HI-TOPK-032 improves the antitumour effects of NK-92MI cells in OVCAR3^Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI-TOPK-032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK-92MI cells with HI-TOPK-032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"629-642"},"PeriodicalIF":3.1,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}