Pharmacology Research & Perspectives最新文献

{"title":"Investigation of the In Vitro Antioxidant, Anticholinesterase, Antiurease, Antityrosinase, and Cytotoxic Properties of a Novel Compound: 4-Methoxy-2-(4-Methoxyphenyl)Benzo[d][1,3,2]Dioxaborole.","authors":"Hamdi Temel, Emine Baydan","doi":"10.1002/prp2.70044","DOIUrl":"10.1002/prp2.70044","url":null,"abstract":"<p><p>In this study, the structure of a new boron compound obtained using 3-methoxy catechol and 4-methoxy phenyl boronic acid was characterized by ¹H, ¹³C NMR, LC-MS-IT-TOF, UV-Vis and FTIR spectroscopy. The antioxidant activities of the newly synthesized compound were evaluated by DPPH free radical scavenging, ABTS quation radical scavenging and CUPRAC copper reducing capacity methods. Anticholinesterase activities were determined by acetylcholinesterase and butyrylcholinesterase enzyme inhibitor assays. Antiurease and antithyrosinase enzyme inhibition activities were also examined. Cytotoxic effects were evaluated on healthy cell lines and breast and colon cancer cell lines using MTT method. The results showed that the synthesized compound has high antioxidant activity. Especially the average antioxidant activity values obtained at 10 μg/mL concentration were found to be statistically significantly (p < 0.05) higher than the reference values of α-TOC and BHT. When the antioxidant activity data (IC₅₀) were compared separately with α-TOC and BHT reference values, the new compound was found to be more effective. In acetylcholinesterase enzyme inhibition, the average activity values were found to be statistically significantly (p < 0.05) higher than the galantamine reference value. However, no statistically significant difference was observed at BChE (% inhibition) level with galantamine reference value. In terms of urease and tyrosinase enzyme inhibition activities, the urease activity of the synthesized compound was statistically significantly (p < 0.05) lower than the thiurea reference value. Tyrosinase activity was statistically significantly (p < 0.05) lower than kojic acid reference values. The synthesized and characterized compound was found to have no toxic effect on healthy cell lines and did not show any cytotoxic effect on breast cancer (MCF-7) and colon cancer (HT-29) cell lines.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70044"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11716980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142953137","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":"Addressing Ethnicity in the Design and Evaluation of an Educational Intervention on Interindividual Variation in Pharmacokinetics.","authors":"Jennifer A Koenig, Olusola Olafuyi, Rakesh Patel","doi":"10.1002/prp2.70073","DOIUrl":"10.1002/prp2.70073","url":null,"abstract":"<p><p>Interindividual variation in pharmacokinetics can occur due to diet, environmental or lifestyle factors, underlying pathology, and gene variants, typically single nucleotide polymorphisms (SNPs). Genetic mechanisms have received the most attention in research and education about ethnic differences in pharmacokinetics. Making this connection between genetics and ethnicity is problematic because it could reinforce the erroneous idea that there is a biological basis to ethnicity. The aim of this work was to design an educational intervention about interindividual variation in pharmacokinetics, explore how students perceive ethnicity and genetic differences prior to the educational intervention, and then assess the impact of the intervention and whether it could influence any misconceptions students might have about ethnicity and genetic similarity. Through the use of questionnaires and focus groups, we found that students typically refer to ethnicity to mean culture and place of origin, whereas in the pharmacological literature, ethnicity is synonymous with racial groups, that is, Black, White, and Asian. Prior to the educational intervention, students tended to expect a genetic mechanism for ethnic differences in drug metabolism and this was reduced after the intervention when a range of other nongenetic mechanisms were presented for interindividual variation. However, students' views about possible underlying mechanisms for ethnic differences in hypertension and about ethnicity more generally were unaffected by the intervention. This highlights the importance of reevaluating the way ethnicity is presented across the medical and medical sciences curriculums to be clear that ethnicity is socially constructed and avoid implying a biological basis.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70073"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256323","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":"Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Inhaled Voriconazole in Healthy Volunteers and Subjects With Stable Asthma.","authors":"Giovanni Caponetti, Federica Sala, Antonio Cervetti, Daniele Colombo, Elena Tiberio, Dave Singh","doi":"10.1002/prp2.70064","DOIUrl":"10.1002/prp2.70064","url":null,"abstract":"<p><p>The aim of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of a novel inhaled formulation of voriconazole (ZP-059). In the single ascending dose part, 4 cohorts of 6 healthy subjects received one dose of inhaled voriconazole (5-40 mg). In the multiple ascending dose part, 3 cohorts of 6 subjects with mild asthma received voriconazole 10 mg twice daily [BID], 20 mg BID or 40 mg once daily. In the 2-period crossover part, 16 subjects with mild to moderate asthma each received one dose of inhaled voriconazole 20 mg and one dose of oral voriconazole 200 mg. A bioanalytical method was developed and validated to simultaneously determine concentrations of voriconazole and its metabolite N-oxide voriconazole in serum and sputum. Inhaled voriconazole was well tolerated with no treatment emergent adverse events (TEAEs) leading to treatment discontinuation. The PK profile of inhaled voriconazole showed rapid absorption, apparent greater than proportional increase in exposure with increasing dose, a consistent half-life across dosing, and large clearance and volume of distribution. Following repeat administration limited accumulation was observed. Systemic exposure following inhaled voriconazole was much lower than following oral voriconazole. Serum data confirmed that voriconazole was extensively metabolized also when administered by inhalation. Sputum data following inhaled voriconazole were limited but demonstrated increasing exposure with increasing dose. The current study shows the newly developed dry powder inhaled formulation of voriconazole to be safe and well tolerated, providing a possible improved treatment approach for patients affected by allergic bronchopulmonary aspergillosis. Trial Registration: ClinicalTrials.gov ID: NCT04229303.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70064"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364462","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":"BCyrius: An Upgraded Version of Cyrius for Accurate CYP2D6 Genotyping From Short-Read Sequencing Data.","authors":"Andreas Halman, Rachel Conyers","doi":"10.1002/prp2.70065","DOIUrl":"10.1002/prp2.70065","url":null,"abstract":"<p><p>Pharmacogenomics is a field of personalized medicine that aims to tailor drug dosing based on the genetics of an individual. The polymorphic and complex CYP2D6 gene is important to analyze because of its role in the metabolism of approximately a quarter of all drugs. Several bioinformatic tools have been developed to genotype CYP2D6 from short-read sequencing data. Among these, Cyrius, a tool specifically designed for CYP2D6 genotyping, has demonstrated high performance across various datasets. However, Cyrius has not been updated in the past 3 years, during which dozens of new star alleles have been identified and some previously defined ones revised. In this work, we simulated all known CYP2D6 haplotypes to assess the ability of Cyrius to identify them. In that dataset, Cyrius was unable to call or misidentified 50 of 360 samples. Given the importance of providing an up-to-date tool, particularly in clinical settings, we present an upgraded version of the tool, named BCyrius, which includes all the missing star alleles as well as revisions to the previously listed ones. BCyrius successfully identified 100% of the currently defined minor star alleles, higher than Cyrius (85.6%) and the two other tested tools, Aldy and StellarPGx, which identified 92.2% and 87.8%, respectively. BCyrius also demonstrated slightly improved performance on a dataset of real biological samples, resulting in a higher call rate while maintaining similar accuracy with Cyrius. In addition to providing genotyping results, BCyrius also reports the predicted phenotype, along with information for each detected haplotype, including population frequencies.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70065"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123398","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":"The Anticonvulsant Effect of Nonsteroidal Anti-Inflammatory Drug, Fenoprofen, in Pentylenetetrazole-Induced Epileptic Rats: Behavioral, Histological, and Biochemical Evidence.","authors":"Maryam Rahimi-Tesiye, Hassan Rajabi-Maham, Vahid Azizi, Abdolkarim Hosseini","doi":"10.1002/prp2.70072","DOIUrl":"10.1002/prp2.70072","url":null,"abstract":"<p><p>This study aimed to evaluate the anticonvulsant properties of fenoprofen on the experimental model of pentylenetetrazole (PTZ)-induced epilepsy. Male Wistar rats were randomly grouped into five, and the kindling model was induced by intraperitoneal injection of PTZ 35 (mg/kg) every other day for 1 month. Aside from the control and PTZ groups, three groups received intraperitoneal injections of fenoprofen at doses of 10, 20, and 40 (mg/kg) before each PTZ injection. Rats were challenged with PTZ 70 (mg/kg) 1 week after kindling development. Then rats were subjected to deep anesthesia, and serum and brain samples were prepared. Oxidative stress (OS) markers (malondialdehyde, superoxide dismutase, and glutathione peroxidase) were measured in serum samples. Hippocampal tissue was used to investigate the relative expression of OS-related genes (nuclear factor [erythroid-derived 2]-like 2 (Nrf2)/heme oxygenase 1 (Hmox1)) and histological studies. Seizure behavior was assessed based on Lüttjohann's score. In treated groups, the number of myoclonic jerks and generalized tonic-clonic seizure (GTCS) duration decreased significantly, while myoclonic jerks and GTCS latency increased compared with the PTZ group. The biochemical evaluation revealed the antioxidative effects of fenoprofen. The decreased expression of Nrf2/HO-1 genes in the PTZ group was reversed after fenoprofen administration. The results of the histological study obtained from Nissl staining in the hippocampal tissue also confirmed the protective effect of fenoprofen. The anticonvulsant effects of fenoprofen seem to be through inhibition of OS-related markers, induction of protective effect in hippocampal tissue, and activation of the Nrf2/HO-1 signaling pathway.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70072"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189899","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":"Remifentanil Ameliorates Lipopolysaccharide-Induced Neuroinflammation by Regulating the Phosphatidylinositol 3-Kinase/Serine-Threonine Protein Kinase/Hypoxia-Inducible Factor 1 Alpha Pathway.","authors":"Mustafa Soner Özcan, Halil Aşcı, Pınar Karabacak, Eyyüp Sabri Özden, Orhan Berk İmeci, Özlem Özmen","doi":"10.1002/prp2.70071","DOIUrl":"10.1002/prp2.70071","url":null,"abstract":"<p><p>There has been scarce research on the potential neuroprotective effects of remifentanil (REM) in septic individuals. We aimed to investigate the role and underlying mechanism of REM in LPS-induced neuroinflammation. Thirty-two rats were randomly divided to control, lipopolysaccharide (LPS), LPS + REM, and REM groups. Depending on the group, 4 h after intraperitoneal administration of LPS or saline, REM or saline was infused intravenously for 40 min. Following the sacrification, blood samples and brain tissues were collected for analysis. Brain tissues (prefrontal cortex, cerebellum, and hippocampus) were stained with hematoxylin and eosin, caspase-3 (Cas-3), and tumor necrosis factor alpha (TNF-α). Quantitative reverse transcription-polymerase chain reaction analysis was used to detect claudin-5 (CLDN5), zonula occludens-1 (ZO-1), phosphatidylinositol 3-kinase (PI3K), serine-threonine protein kinase (AKT), and hypoxia-inducible factor 1 alpha (HIF-1α) gene expression levels. Histopathologic and immunohistochemical analyses showed that REM treatment improved LPS-induced histological changes. REM does not reduce TOS and OSI levels or increase TAS levels, suggesting that it is ineffective through oxidative stress. LPS-induced changes in gene expression levels (PI3K, AKT, HIF-1α, and CLDN5) were also reversed by REM. REM was found to prevent neuroinflammation, and apoptosis by restoring blood-brain barrier, and regulating the PI3K/AKT/HIF-1α pathway. These findings suggest that REM is protective against neuroinflammation.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70071"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080783","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":"Dementia and Alzheimer's Disease Associated With Aromatase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase).","authors":"María Teresa Yuste, María Sainz-Gil, Elisa Escudero, Pedro Marín","doi":"10.1002/prp2.70075","DOIUrl":"10.1002/prp2.70075","url":null,"abstract":"<p><p>Aromatase inhibitors are used for patients with hormone-receptor positive breast cancer. Alzheimer's disease is the most prevalent cause of dementia. Several studies have suggested an association between the use of aromatase inhibitors and the development of Alzheimer's disease. The objective of this study was to identify potential pharmacovigilance signals associated with dementia and Alzheimer's disease and third-generation aromatase inhibitors in menopausal and postmenopausal women. VigiBase, the global database of individual case safety reports of the World Health Organization, was used to investigate this possible association. A disproportionality analysis was performed for women aged 45 years and older. The reporting odds ratio (ROR) and its 95% CI for reporting dementia are exemestane, 2.08 (1.35-3.19); anastrozole, 1.59 (1.09-2.32); and letrozole, 1.43 (1.05-1.95) and for Alzheimer's disease are exemestane, 0.94 (0.30-2.92); anastrozole: 2.63 (1.55-4.45); and letrozole, 1.33 (0.76-2.35). For senile dementia, only letrozole has cases, with an ROR of 6.77 (2.51-18.31). Signals of disproportionate reporting have been observed between the occurrence of dementia, dementia Alzheimer's type, and senile dementia with aromatase inhibitors, which is in line with estrogen functions and aromatase activity, as well as the findings from preclinical studies. Additional research is required to elucidate this intricate matter.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70075"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364460","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":"Mechanisms and pharmacotherapy of cancer cachexia-associated anorexia.","authors":"Ryosuke Sato, Guilherme Wesley Peixoto da Fonseca, Willian das Neves, Stephan von Haehling","doi":"10.1002/prp2.70031","DOIUrl":"10.1002/prp2.70031","url":null,"abstract":"<p><p>Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused by underlying illnesses such as cancer, heart failure, and renal failure. Inflammation, insulin resistance, increased muscle protein degradation, decreased food intake, and anorexia are the primary pathophysiological drivers of cachexia. Cachexia causes physical deterioration and functional impairment, loss of quality of life, lower response to active treatment, and ultimately morbidity and mortality, while the difficulties in tackling cachexia in its advanced phases and the heterogeneity of the syndrome among patients require an individualized and multidisciplinary approach from an early stage. Specifically, strategies combining nutritional and exercise interventions as well as pharmacotherapy that directly affect the pathogenesis of cachexia, such as anti-inflammatory, metabolism-improving, and appetite-stimulating agents, have been proposed, but none of which have demonstrated sufficient evidence to date. Nevertheless, several agents have recently emerged, including anamorelin, a ghrelin receptor agonist, growth differentiation factor 15 neutralization therapy, and melanocortin receptor antagonist, as candidates for ameliorating anorexia associated with cancer cachexia. Therefore, in this review, we outline cancer cachexia-associated anorexia and its pharmacotherapy, including corticosteroids, progesterone analogs, cannabinoids, anti-psychotics, and thalidomide which have been previously explored for their efficacy, in addition to the aforementioned novel agents, along with their mechanisms.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70031"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056093","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":"The N-Acetyltransferase 2 Polymorphism and Susceptibility to Inflammatory Bowel Disease: A Case-Control Study.","authors":"Pawel Petryszyn, Grzegorz Zurakowski, Robert Dudkowiak, Marta Machowska, Agnieszka Gruca, Pawel Ekk-Cierniakowski, Jadwiga Skretkowicz, Elzbieta Poniewierka, Anna Wiela-Hojenska, Krystyna Glowacka","doi":"10.1002/prp2.70040","DOIUrl":"10.1002/prp2.70040","url":null,"abstract":"<p><p>The enzyme N-acetyltransferase 2 (NAT2) plays an important role in metabolism and detoxification of xenobiotics, including carcinogens and medications. We aimed to assess the contribution of the NAT2 polymorphism to susceptibility to inflammatory bowel disease (IBD) in the Polish population. The study involved 101 IBD patients and 100 healthy controls. The NAT2 gene mutations at positions 481T, 803G, 590A, and 857A were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique on peripheral blood DNA samples. Carriers of the NAT2*5 allele had a greater chance of developing Crohn's disease (CD) (OR = 1.73, 95% CI 1.06-2.83). Also, the NAT2*4/5 genotype was more prevalent in CD patients (OR = 2.77, 95% CI 1.17-6.57). When compared to the control group, the prevalence of the NAT2*4/6 genotype in the IBD patient population was significantly lower (10.9% vs. 30.0%, p < 0.01). In the Polish population, polymorphism in the NAT2 gene may potentially alter susceptibility to IBD.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70040"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885668","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":"Dynamics of thrombin generation: Filling the gap between the system pharmacology theory and clinical practice in clinical pharmacology and therapeutics.","authors":"Leire Ruiz, Sebastian Jaramillo, Andrea Calvo, M A Torrente, Dolors Tassies, J C Reverter, Annabel Blasi, Iñaki Troconiz","doi":"10.1002/prp2.70014","DOIUrl":"10.1002/prp2.70014","url":null,"abstract":"<p><p>Mathematical models of thrombin generation (TG) that have been developed are based on a systems biology approach. Although this approach provides important information about the coagulation system, its clinical applicability is limited by its complexity and number of input variables required. The aim of this study was to develop a semimechanistic model able to describe TG in trauma and control patients. A dataset containing longitudinal data of TG assays and coagulation factors from 40 trauma patients and 20 control patients was used for model building. The model considered three fundamental processes: the degradation of tissue factor (TF) through a first-order process, the activation of factor II by the TF through a first-order process, and the degradation of thrombin through a first-order process. Model fitting was performed using a nonlinear mixed-effects approach. The condition of the patient (trauma and control) and coagulation factors were modelled as covariates. Model building demonstrated the presence of two additional processes that improved the predictive capacity of the model: the activation of factor II by TF governed by a second-order constant and, a mechanism of factor II activation by TF characterized by a 7-compartment transit chain governed by a second-order constant. In the covariate model only the inclusion of patient condition was significant. Model evaluation demonstrated excellent performance in describing the temporal pattern of TG in trauma and control patients. Thrombin generation can be adequately modelled using a semimechanistic approach. Its application in practice could help to better assess the risk of hemorrhage and/or thrombosis in different settings.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70014"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910056","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}