Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Antagonism of prostate α_1A-adrenoceptors by verapamil in human prostate smooth muscle contraction.","authors":"Sheng Hu, Guangyang Liu, Oluwafemi Kale, Wenbin Zhu, Yajie Xu, Patrick Keller, Philipp Weinhold, Alexander Tamalunas, Christian G Stief, Martin Hennenberg","doi":"10.1016/j.jpet.2025.103603","DOIUrl":"10.1016/j.jpet.2025.103603","url":null,"abstract":"<p><p>Voiding symptoms and hypertension are common comorbidities. α₁-Blockers are the first-line medication for the treatment of voiding symptoms. Off-target antagonism of α₁-adrenoceptors by cardiovascular drugs may add to the side effects of α₁-blockers but may also hold the potential to avoid polypharmacy. Here, we examined α₁-adrenergic antagonism by the calcium channel blocker verapamil in the human prostate. Prostate tissues were obtained from radical prostatectomy. Contractions were examined by organ bath. Verapamil caused concentration-dependent inhibitions of α₁-adrenergic and electric field stimulation-induced contractions and increases of EC₅₀ values for α₁-agonists. E_max values for phenylephrine, methoxamine, noradrenaline, and electric field stimulation were decreased by 41%, 17%, 41%, and 39% by 1-μM verapamil and by 62%, 36%, 51%, and 93% by 10-μM verapamil. EC₅₀ values for phenylephrine, methoxamine, and noradrenaline were increased by 0.47, 0.36, and 0.18 orders of magnitude by 1-μM verapamil and by 0.83, 1.22, and 1.54 orders of magnitude by 10-μM verapamil. The 100-nM verapamil increased the EC₅₀ values for noradrenaline by 0.43 magnitudes but only slightly (<0.2 magnitudes) for phenylephrine and methoxamine. U46619-induced contractions were unchanged by 10-μM verapamil. E_max values for endothelin-1-induced contractions were reduced by 14% by 10-μM verapamil. Antagonism of α₁-adrenoceptors by verapamil in the human prostate begins at concentrations corresponding to plasma concentrations at high doses. Improvements of voiding symptoms through this antagonism may help to avoid polypharmacy in elderly populations, but application in BPH may be limited by drug-drug interactions and additive side effects. SIGNIFICANCE STATEMENT: Our findings align verapamil concentrations antagonizing α₁-adrenergic contractions of human prostate tissues with known plasma levels. Improvements of voiding symptoms appear possible, but application in benign prostatic hyperplasia may be limited by drug-drug interactions and additive side effects.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103603"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potentiation of group III metabotropic glutamate receptors positively affects neurophysiological features in a mouse model of Rett syndrome.","authors":"Hong-Wei Dong, Kelly Weiss, Jonathan W Dickerson, Mac J Meadows, Irene Zagol-Ikapitte, Olivier Boutaud, Jerri M Rook, Jeffrey L Neul, Colleen M Niswender","doi":"10.1016/j.jpet.2025.103602","DOIUrl":"10.1016/j.jpet.2025.103602","url":null,"abstract":"<p><p>Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Genetic restoration of MECP2 in mice can reverse phenotypes, providing hope for disease-modifying therapies in the disease. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials (AEPs), that correlate with disease severity, suggesting potential as translatable biomarkers. We have identified reductions in the expression and function of the group III metabotropic glutamate receptor 7 (mGlu₇), a G protein-coupled receptor regulating presynaptic neurotransmitter release, in both human and mouse RTT brains. Additionally, treatment of RTT mice with a positive allosteric modulator (PAM) of the group III mGlu receptors (VU0422288) improves behavioral phenotypes, most likely via mGlu₇ potentiation. To evaluate whether VU0422288 treatment modulates neurophysiological biomarkers, we acutely treated RTT mice with VU0422288 at 3,10, and 30 mg/kg and assessed neurophysiological features. VU0422288 treatment caused increases in AEP peak amplitudes in RTT mice but not in wild-type controls, with no effect on basal electroencephalogram power. Treatment with a different compound, ADX88178, a PAM that activates the mGlu_{4, 6}_{and 8} receptors, did not affect neurophysiological assessments, suggesting that the target of VU0422288 is likely mGlu₇. These findings suggest that neurophysiological features, like AEP, have potential as sensitive and quantitative biomarkers that may be useful in evaluating mGlu₇ PAMs and other pharmacological interventions as novel RTT treatment strategies. SIGNIFICANCE STATEMENT: Correlations between neurophysiological features and disease severity in Rett syndrome suggest their potential as translatable biomarkers sensitive to pharmacological modulation. This study demonstrates that potentiation of group III metabotropic glutamate receptors improves neurophysiological features in Rett syndrome mice.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103602"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Death receptor 5 agonists mitigate cardiac pathology in a chronic isoproterenol-induced cardiac remodeling and dysfunction.","authors":"Miles A Tanner, Katrina Dougherty, Laurel A Grisanti","doi":"10.1016/j.jpet.2025.103600","DOIUrl":"10.1016/j.jpet.2025.103600","url":null,"abstract":"<p><p>Heart failure is a leading cause of death. Despite the economic and health burden, few recent therapeutic advances have been made and current therapies alleviate the symptoms, but minimally impact mortality, highlighting the need for identifying novel therapeutic targets. Death receptor 5 (DR5) has been studied extensively in cancer for its role in inducing apoptosis in transformed cells. However, DR5 is ubiquitously expressed, including in the heart, where its function is poorly understood. Clinical studies have associated DR5 and its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with heart failure due to multiple etiologies. Previous studies in cardiac cells and mouse models have demonstrated that DR5 promotes eccentric cardiac hypertrophy through ERK1/2-dependent mechanisms and the apoptosis of myofibroblasts. ERK1/2 signaling has been associated with prosurvival mechanisms in cardiomyocytes suggesting DR5 agonism may be a novel therapeutic approach to outcomes in heart failure. We hypothesized that activation of DR5 will be protective in heart failure. Using a chronic isoproterenol administration model, mice were administered a DR5 agonist and progression of cardiac dysfunction was monitored by echocardiography. Cardiac remodeling was assessed by histology and prohypertrophic and profibrotic marker expression. Specificity of these responses was confirmed with DR5 knockout and the involvement of ERK1/2 signaling was confirmed using pharmacological inhibitors. DR5 agonists decreased cardiac remodeling and improved contractility in response to isoproterenol, which was prevented by ERK1/2 inhibition. These findings demonstrate that activation of DR5 reduces the progression of cardiac remodeling and dysfunction and may be a novel therapeutic target for heart failure treatment. SIGNIFICANCE STATEMENT: Death receptor 5 (DR5) is expressed in cardiomyocytes where its function is poorly defined and clinically, DR5 has been associated with heart failure development and severity. Previous studies show in healthy cardiomyocytes, DR5 activates ERK1/2 signaling, causing eccentric hypertrophy, which are associated with cardioprotection during heart failure. This study investigates the therapeutic potential of targeting DR5 and demonstrates that, in a chronic isoproterenol-infusion model of cardiac dysfunction, DR5 activation reduces maladaptive cardiac remodeling and preserves function through ERK1/2-dependent mechanisms.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103600"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More than just a prime: Cocaine gives monkeys the munchies.","authors":"Lydia Gordon-Fennell, Paul E M Phillips","doi":"10.1016/j.jpet.2025.103580","DOIUrl":"10.1016/j.jpet.2025.103580","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103580"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1, first-in-human, open label, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of stabilized isoamyl nitrite nasal spray in healthy adult participants.","authors":"David Cassie, Mila Mirceta, Jing Tian, Melisa Bellani, Erika Juanitez, Jessica McLeod, Vanja Komlenovic, Bojan Drobic, Bob Warnock, Vladimir Savransky, Vira Artym, Daniel Hill, Christopher Holstege, Jerry Punch, William Smith, David Wyatt","doi":"10.1016/j.jpet.2025.103584","DOIUrl":"10.1016/j.jpet.2025.103584","url":null,"abstract":"<p><p>Stabilized isoamyl nitrite (SIAN) is a novel small molecule, therapeutic candidate for the treatment of cyanide poisoning. SIAN improves survival and has a demonstrated pharmacodynamic (PD) effect in cyanide challenged nonhuman primates. Here, we report results of phase 1, first-in-human study evaluating the safety, tolerability, pharmacokinetic (PK), and PD of SIAN nasal spray in healthy human subjects (NCT05194358). SIAN was intranasally administered in ascending doses at 2 sites in Texas and Tennessee in the United States. A total of 47 subjects were enrolled across 7 dose cohorts evaluating single doses from 20 to 300 μL. Following the dosing of sentinels in each cohort, safety, PK, and PD data were interpreted by a Safety Monitoring Committee to permit dosing of additional subjects in the cohort or escalation to the next dose level. Isoamyl alcohol peak plasma concentrations were reached within 2 minutes and were highest after a 250 μL dose (125 μL/nostril). This trend was also observed for PD parameters, including a metHB peak at 2 minutes with associated increase in heart rate and systolic and diastolic blood pressure. SIAN was generally well tolerated, no serious or severe drug-related effects were observed, and there were no clinically significant changes in vitals or laboratory parameters. We conclude that SIAN, a potential new treatment for cyanide poisoning, was safe, well tolerated, and showed a relationship between PK and PD parameters at the doses tested. SIGNIFICANCE STATEMENT: This is the first-in-human clinical study to evaluate intranasal stabilized isoamyl nitrite, which was shown to be safe, well tolerated, and to elicit a measurable pharmacokinetic and pharmacodynamic response in healthy human subjects at the doses tested. This study paves the way for investigating stabilized isoamyl nitrite further as a potential emergency treatment for cyanide poisoning.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103584"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional transfer of pritelivir across term human placenta and its effect on placental functions.","authors":"Valentina F Bryant, Svetlana L Patrikeeva, Xiaoming Wang, Tatiana N Nanovskaya","doi":"10.1016/j.jpet.2025.103581","DOIUrl":"10.1016/j.jpet.2025.103581","url":null,"abstract":"<p><p>Genital herpes in pregnancy is treated with nucleoside analog drugs such as acyclovir to reduce the risk of mother-to-neonate transfer of the virus. Pritelivir is a novel anti-herpes simplex virus drug that is effective against acyclovir-resistant viral strains and is currently in phase 3 clinical trial for nonpregnant subjects. Here, we determined bidirectional transfer of pritelivir across dually perfused term human placental lobule and its effect on placental tissue viability and functionality ex vivo. We also assessed potential cytotoxicity of pritelivir in vitro using human choriocarcinoma-derived trophoblast-like cells (BeWo, b30 clone) and human umbilical vein endothelial cells. Our data demonstrated the transfer of pritelivir across the placenta ex vivo from the maternal to the fetal circuit and vice versa. Clearance index of pritelivir (ie, the transfer of pritelivir normalized to the transfer of a freely diffusible reference compound antipyrine) in the fetal-to-maternal direction (0.98 ± 0.07, n = 9) exceeded its clearance index in the maternal-to-fetal direction (0.86 ± 0.08, n = 9, P = .006), suggesting involvement of mechanisms other than diffusion in the placental disposition of this drug (possibly, efflux membrane transporters P-glycoprotein and breast cancer resistance protein that accept pritelivir as a substrate in vitro). Although our data suggested plausible fetal exposure to the drug, pritelivir did not affect the production of lactate, the consumption of glucose and oxygen, and the release of human chorionic gonadotropin from the perfused placental tissue, indicating its favorable safety profile. Moreover, pritelivir did not alter the viability of the tested cells in vitro. SIGNIFICANCE STATEMENT: Preclinical data on placental disposition of pritelivir are crucial to advance the development of this novel antiherpetic drug for its use in pregnancy. The results revealed bidirectional transfer of pritelivir across dually perfused term human placenta ex vivo. Although fetal exposure to the drug is plausible, pritelivir did not impact the viability and functionality of the placenta. Higher transplacental transfer of pritelivir in the fetal-to-maternal direction rather than maternal-to-fetal direction suggested the involvement of placental membrane transporters.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103581"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic crosstalk between carbachol, a muscarinic receptor agonist, and the long-acting β₂-adrenoceptor agonist, indacaterol, in human airway epithelial cells.","authors":"Varuna Jayasinghe, Radhika Joshi, Taruna Joshi, Tamkeen U Paracha, Cora Kooi, Mahmoud M Mostafa, Carla M T Bauer, Steven J Charlton, Oleg Iartchouk, Ashley Maillet, Melody K Morris, Vera M Ruda, David A Sandham, Yanqun Wang, Robert Newton, Mark A Giembycz","doi":"10.1016/j.jpet.2025.103579","DOIUrl":"10.1016/j.jpet.2025.103579","url":null,"abstract":"<p><p>Many patients with chronic obstructive pulmonary disease are susceptible to recurrent exacerbations. In this study, we hypothesized that endogenous acetylcholine (ACh) may act as a proinflammatory mediator because long-acting muscarinic receptor antagonists protect against exacerbations, which have an inflammatory basis. This possibility was explored by determining if carbachol (CCh), a stable ACh analog, was a genomic stimulus in BEAS-2B bronchial epithelial cells. The ability of CCh to interact with indacaterol (Ind), a long-acting β₂-adrenoceptor agonist, was also assessed given that (1) sympathomimetic bronchodilators can promote adverse gene expression changes in airway structural cells, and (2) crosstalk between β₂-adrenoceptor and Gq-coupled muscarinic receptor agonists is well described. Unlike Ind, which induced 624 unique genes, CCh was a relatively weak genomic stimulus, implying that ACh may not behave as a proinflammatory mediator as hypothesized. Nevertheless, checkerboard assays using BEAS-2B cells expressing a cAMP-response element luciferase reporter determined that CCh interacted with Ind in a supra-additive manner and that this interaction was replicated on 39 Ind-regulated genes. Functional annotation of the Ind-regulated transcriptomes identified \"transcription\" and \"signalling\" as the dominant themes, with gene ontology terms associated with \"inflammation\" and \"immune processes\" being highly represented. A comparable gene ontology signature was obtained when Ind and CCh were combined; however, the number, magnitude and duration of gene expression changes were significantly enhanced. If genomic interactions occur between a long-acting β₂-adrenoceptor agonist and ACh in vivo, then they may enhance the expression of adverse-effect genes that could maintain, or even augment, features of lung pathology in chronic obstructive pulmonary disease. SIGNIFICANCE STATEMENT: Long-acting muscarinic receptor antagonists reduce exacerbation risk in chronic obstructive pulmonary disease, implying the etiology could have an inflammatory basis mediated by acetylcholine. However, in BEAS-2B cells, carbachol was a weak genomic stimulus, although it enhanced changes in indacaterol-regulated gene expression. Functional annotation of carbachol + indacaterol-regulated genes identified gene ontology terms associated with several themes, including inflammation. Interaction between a long-acting β₂-adrenoceptor agonist and endogenous acetylcholine could, paradoxically, augment airway inflammation in patients with chronic obstructive pulmonary disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103579"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of dose-exposure-response relationship for adeno-associated virus-mediated delivery of antibody genes.","authors":"Aneesh Rajwade, Shufang Liu, Mokshada Kumar, Avanobe Ghobrial, Sara Hahn, Dhaval K Shah","doi":"10.1016/j.jpet.2025.103601","DOIUrl":"10.1016/j.jpet.2025.103601","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based gene therapies have advanced significantly, yet the pharmacology of these therapies, particularly the relationship between dose and transgene expression, remains incompletely understood. Here, we investigated the dose-response dynamics of AAV8 vectors encoding an antibody (trastuzumab) gene in C57BL/6 mice to assess virus pharmacokinetics, transgene expression, liver toxicity, and immunogenicity across a broad dose range (1E8-1E13 vector genomes/mouse). Whole-body viral pharmacokinetics data revealed dose nonproportionality, with higher doses leading to less than proportional increases in AAV exposure across most tissues, except for the spleen, which exhibited a more than proportional increase. Plasma transgene concentrations demonstrated a sigmoidal dose-response relationship, with Emax of ∼ 8000 nM and EC50 of ∼8E9 vector genomes, indicating saturation at higher doses. Immune responses to AAV8 were dose-dependent, with IgM titers peaking on day 2 and IgG titers appearing by day 21, both escalating with increasing doses. Elevated aspartate aminotransferase and alanine aminotransferase levels at higher doses indicate a hepatotoxic effect. These findings suggest that the nonlinear dose-exposure relationship stems from saturable tissue distribution, nonlinear transgene production, or heightened immune activation at higher doses. Importantly, the nonlinearity in translational efficiency and an increased risk for immunogenicity and hepatotoxicity at higher dose levels underscore the critical need to optimize AAV dosing to balance efficacy and safety. These data provide valuable insights into the pharmacology of AAV gene therapies and offer a framework for determining optimal dosing strategies that maximize therapeutic benefit while minimizing toxicity and immunogenicity. SIGNIFICANCE STATEMENT: The research presented here demonstrates that there is an optimal dose for adeno-associated virus-based therapies and exceeding this dose might lead to more immunogenicity, more toxicity, and reduced transgene expression.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103601"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disulfiram activation of prostaglandin E2 synthesis: a novel antifibrotic mechanism in pulmonary fibrosis.","authors":"Xiaolin Pei, Fangxu Zheng, Yin Li, Xiaobo Li, Zhoujun Lin, Xiao Han, Zhenhuan Tian, Ke Cao, Dunqiang Ren, Chenggang Li","doi":"10.1016/j.jpet.2025.103588","DOIUrl":"10.1016/j.jpet.2025.103588","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by the pathological replacement of alveolar structures with thickened, inelastic fibrous tissue, which significantly hinders gas exchange in the lungs. Disulfiram (DSF), a Food and Drug Administration-approved drug for alcohol dependence, has shown potential in various diseases. This study investigates the effects of DSF on IPF and its mechanisms, focusing on the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. Utilizing primary diseased human lung fibroblast-IPF cells and A549 cells induced with transforming growth factor-beta 1 to model epithelial-mesenchymal transition (EMT), we employed a battery of in vitro assays to assess cellular viability, migratory capacity, and the expression of fibrosis-related genes and proteins. To further substantiate our in vitro findings, a bleomycin-induced mouse model of IPF was treated with DSF, and subjected to a comprehensive evaluation of pulmonary function, histological examination, hydroxyproline assay, and western blot analysis to quantify the extent of fibrosis. DSF reduced cell viability and migration in fibrotic cell models. It increased COX-2 and PGE2 levels, regulated EMT, and extracellular matrix collagen deposition. In vivo, DSF improved pulmonary function and reduced EMT and extracellular matrix accumulation in mice. The COX-2/PGE2 axis was identified as a critical mediator of DSF's effects. DSF exhibits antifibrotic properties in IPF by modulating the COX-2/PGE2 signaling pathway. This study provides a novel therapeutic strategy for IPF and highlights the potential of repurposing DSF for clinical use in this context. SIGNIFICANCE STATEMENT: Disulfiram shows promise in treating idiopathic pulmonary fibrosis by targeting the cyclooxygenase-2/prostaglandin E2 pathway, offering a new therapeutic strategy and highlighting its potential for repurposing in this context.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103588"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on collagen-induced arthritis rodent studies.","authors":"Rui Li, Roger Gifford, Peter Symanowicz, Cara M M Williams, Martin Hegen","doi":"10.1016/j.jpet.2025.103589","DOIUrl":"10.1016/j.jpet.2025.103589","url":null,"abstract":"<p><p>Setting a clinically efficacious dose in the preclinical stage is an important but challenging task in developing new therapies, including small-molecule kinase inhibitors for rheumatoid arthritis (RA). Besides pharmacokinetics and potency, another key component in determining the efficacious dose of a small molecule targeted therapy is the target inhibition level required for efficacy, which few established approaches can predict based on preclinical data. Using collagen-induced arthritis rodent data, we aimed to establish a translational approach in predicting the lowest efficacious target inhibition level in patients with RA, assuming that similar levels of target inhibition are required for efficacy in both patients and animal models. Target inhibition levels of tofacitinib, zimlovisertib, and 3 literature kinase inhibitors at efficacious and inefficacious doses were compared between patients and rodents using a new approach based on average inhibition level (I_AVG). For comparison purposes, classic approaches based on average, maximal, and minimal exposures and durations with exposure above IC₃₀, IC₅₀, IC₇₀, and IC₉₀ are also included in our analysis. We found that the lowest I_AVG required for efficacy was generally consistent between humans and rodents. Overall, the I_AVG-based approach led to a better alignment between rodent and human efficacy and is more universally applicable than other approaches. For future kinase inhibitors in discovery or development, I_AVG-based rodent-to-human translation can be used to identify the target inhibition level required for efficacy and corresponding efficacious dose in patients with RA. SIGNIFICANCE STATEMENT: Identifying the target inhibition level required for clinical efficacy in the preclinical stage is important in developing new therapies. However, there are few established approaches aiming to predict this level based on preclinical data. Using data from kinase inhibitors for rheumatoid arthritis, this study proposed a rodent-to-human translation approach. The established translation helps to predict the efficacious inhibition level and corresponding efficacious dose for future kinase inhibitors for rheumatoid arthritis. The approach may also be applicable to other small-molecule targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103589"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}