Journal of pharmacology & clinical toxicology最新文献

A Pharmacokinetic/Toxicodynamic Model of Cisplatin Nephrotoxicity Using the Kidney Injury Molecule-1 Biomarker. 基于肾损伤分子-1生物标志物的顺铂肾毒性药代动力学/毒理学模型

Journal of pharmacology & clinical toxicology Pub Date : 2024-01-01 Epub Date: 2024-09-20 DOI: 10.47739/pharmacology1184

Lauren E Thompson, Avisek Ghimire, Xia Wen, Christine Kim, Juliana Choza, Cathleen L Doherty, Brian T Buckley, Daniel W Bowles, Cindy L O'Bryant, David G Pfister, Edgar A Jaimes, Lauren M Aleksunes, Melanie S Joy

{"title":"A Pharmacokinetic/Toxicodynamic Model of Cisplatin Nephrotoxicity Using the Kidney Injury Molecule-1 Biomarker.","authors":"Lauren E Thompson, Avisek Ghimire, Xia Wen, Christine Kim, Juliana Choza, Cathleen L Doherty, Brian T Buckley, Daniel W Bowles, Cindy L O'Bryant, David G Pfister, Edgar A Jaimes, Lauren M Aleksunes, Melanie S Joy","doi":"10.47739/pharmacology1184","DOIUrl":"10.47739/pharmacology1184","url":null,"abstract":"Cisplatin is a platinum-based chemotherapeutic that causes acute kidney injury in over 30% of patients. The aim of this study was to develop a population pharmacokinetic/toxicodynamic (PKTD) model of cisplatin-induced kidney injury that incorporated plasma total platinum and urinary kidney injury molecule-1 (KIM-1) concentrations. Cancer patients receiving their first or second round of cisplatin-containing chemotherapy (n=39) were prospectively randomized to a 5-HT3 antagonist (5-HT3A) antiemetic (ondansetron, granisetron, or palonosetron) and had blood and urine collected over 10 days. Plasma concentrations of total platinum and urinary concentrations of KIM-1 were used in the development of a nonlinear mixed effect population PKTD model using Phoenix® NLME (v8.3, Certara Inc.). A stepwise search was used to test potential covariates that influenced PKTD parameters. A two-compartment model best described the plasma total platinum concentration vs. time data and was expanded to an effect compartment PKTD model incorporating urinary KIM-1 concentrations. Significant covariate effects for the PKTD model included previous cisplatin exposure on the volume of the central compartment (V1), 5-HT3A antiemetic treatment on the volume of the peripheral compartment (V2), and baseline urinary KIM-1 levels on the maximum effect (Emax) parameter. The model demonstrated that ondansetron-treated subjects had a 163% increase in exposure to plasma total platinum, a 94% increase in urinary KIM-1 maximum concentrations, and a 235% increase in total urinary KIM-1 excretion compared to palonosetron-treated subjects, suggesting that palonosetron may be a preferred 5-HT3A to reduce the risk of cisplatin-induced kidney injury.","PeriodicalId":90230,"journal":{"name":"Journal of pharmacology & clinical toxicology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ibuprofen and risk of hypoglycemia in diabetic and non-diabetic consumers: analysis of international pharmacovigilance data 布洛芬与糖尿病和非糖尿病消费者的低血糖风险:国际药物警戒数据分析

Journal of pharmacology & clinical toxicology Pub Date : 2021-01-01 DOI: 10.47739/pharmacology.1154

Mulugeta Russom, Filipos Yohannes, Abel Tekle, Ruth Ghirmay

{"title":"Ibuprofen and risk of hypoglycemia in diabetic and non-diabetic consumers: analysis of international pharmacovigilance data","authors":"Mulugeta Russom, Filipos Yohannes, Abel Tekle, Ruth Ghirmay","doi":"10.47739/pharmacology.1154","DOIUrl":"https://doi.org/10.47739/pharmacology.1154","url":null,"abstract":"Introduction: Ibuprofen was associated with hypoglycemia in a single published case report in a diabetic patient. Ibuprofen, however, has never been associated so far with hypoglycemia in previously healthy non-diabetic individuals and thus, it is not listed as adverse effect in its summary of product characteristics approved by major regulatory authorities. Objective: This study was conducted to assess the causal relationship between ibuprofen and hypoglycemia in diabetic and non-diabetic individuals. Materials and Methods: Analysis of the literature and the WHO global database of individual case safety reports, VigiBase, was made to explore evidence on the association of ibuprofen and hypoglycemia. The unpublished data and the currently availablepublished toxicological, biological, clinical and epidemiological evidence, if any, was systematically organized using Austin Bradford Hill criteria, causality assessment framework, to assess the causal link between ibuprofen and hypoglycemia. Results: In VigiBase, there were 125 cases of hypoglycemia associated with ibuprofen, reported from 19 countries. About 50% had history of diabetes. Ibuprofen was reported as sole suspect in 36.8% of the cases and the only drug administered in18.4%. Hypoglycemia resolved following discontinuation of ibuprofen in 21.6% and recurred in three patients with rechallenge. Outcome was fatal in 10.5%. Where ibuprofen was solely administered, median time-to-onset of hypoglycemia was one-day following administration of the drug. In an experimental study, a significant decrease in blood glucose level was observed at a higher dose of ibuprofen compared to a low-dose. Conclusion: Currently available totality of evidence reflects a possible causal association between ibuprofen and hypoglycemia that need to be substantiated with further studies.","PeriodicalId":90230,"journal":{"name":"Journal of pharmacology & clinical toxicology","volume":"406 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90665447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New Sites for Old Suspects: Environmental Allosteric Modifiers of Nuclear Hormone Receptors. 核激素受体的环境变构调节剂。

Journal of pharmacology & clinical toxicology Pub Date : 2015-01-17

Bk Asare, Rv Rajnarayanan

引用次数: 0

Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency. 万古霉素在肾功能不全儿童中基于人群的药代动力学模型。

Journal of pharmacology & clinical toxicology Pub Date : 2014-01-01

Jennifer Le, Florin Vaida, Emily Nguyen, Felice C Adler-Shohet, Gale Romanowski, Jiah Kim, Tiana Vo, Edmund V Capparelli

{"title":"Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency.","authors":"Jennifer Le, Florin Vaida, Emily Nguyen, Felice C Adler-Shohet, Gale Romanowski, Jiah Kim, Tiana Vo, Edmund V Capparelli","doi":"","DOIUrl":"","url":null,"abstract":"Background: Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.Methods: Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.Results: Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.Conclusion: Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.","PeriodicalId":90230,"journal":{"name":"Journal of pharmacology & clinical toxicology","volume":"2 1","pages":"1017-1026"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191860/pdf/nihms578155.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32742701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis. 增强F508del校正的效力:囊性纤维化药物开发的多层联合方法。

Journal of pharmacology & clinical toxicology Pub Date : 2013-08-28

Emily F Kirby, Ashley S Heard, X Robert Wang

{"title":"Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis.","authors":"Emily F Kirby, Ashley S Heard, X Robert Wang","doi":"","DOIUrl":"","url":null,"abstract":"With better understanding of the cellular and molecular pathophysiology underlying cystic fibrosis (CF), novel drugs are being developed that specifically target the molecular defects of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel on the plasma membrane that causes CF. Starting with cell-based high-throughput screening, small molecules have been identified that are able to fix specific molecular defects of various disease-causing CFTR mutants. With the successful development of ivacaftor, a \"potentiator\" that enhances CFTR chloride channel activity, new types of small-molecule compounds that \"correct\" the misfolding and misprocessing of the most common CF-causing mutation, F508del, are actively being sought for. Recent studies focused on the potential mechanisms of action of some of the investigational CFTR \"correctors\" shed new light on how the F508del mutant can be targeted in an attempt to ameliorate the clinical symptoms associated with CF. A multi-layer combinational approach has been proposed to achieve the high-potency correction necessary for significant clinical outcome. The mechanistic insights obtained from such studies will shape the future therapeutics development for the vast majority of CF patients.","PeriodicalId":90230,"journal":{"name":"Journal of pharmacology & clinical toxicology","volume":"1 1","pages":"1007"},"PeriodicalIF":0.0,"publicationDate":"2013-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026356/pdf/nihms-572195.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32364014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0