Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Corrigendum to \"Sonorheometry parameters during dabigatran reversal with idarucizumab for major bleeding\" [The Journal of Pharmacology and Experimental Therapeutics 392 (2025) 103605].","authors":"Dorian Teissandier, Geoffroy Rousseau, Camille Lucchini, Boris Teulade, Camille Joly, Jeannot Schmidt, Bruno Pereira, Aurélien Lebreton, Farès Moustafa","doi":"10.1016/j.jpet.2025.103643","DOIUrl":"10.1016/j.jpet.2025.103643","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103643"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512069","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":"Absorption, distribution, metabolism, and excretion of [¹⁴C]SHEN211, a nonpeptidic small-molecule 3CL^pro inhibitor, in rats.","authors":"Zihao Zhang, Mengting Jia, Feiyu Wang, Chen Yang, Huanhuan Shi, Yali Yuan, Zhuoran Tian, Congmei Ming, Jinwen Huang, Junfang Pan, Xiaokun Shen, Yuandong Zheng, Xingxing Diao","doi":"10.1016/j.jpet.2025.103623","DOIUrl":"10.1016/j.jpet.2025.103623","url":null,"abstract":"<p><p>SHEN211 is a selective 3-chymotrypsin-like protease inhibitor that can protect against severe acute respiratory syndrome coronavirus 2. It is currently being assessed in clinical trials in China, but few studies have reported its metabolism in preclinical and clinical settings. This study used radioactive isotope labeling to investigate the absorption, distribution, metabolism, and excretion of SHEN211 in rats. After a single intragastric administration of 2.0 mg/kg (100 μCi/kg) of [¹⁴C]SHEN211 in rats, the inhibitor was rapidly absorbed, with feces being the primary route of excretion. The results of tissue distribution indicated that SHEN211-related components were mainly concentrated in the liver. In total, 11 metabolites were identified in rat plasma, urine, feces, and bile, and SHEN211 was the major drug-related component in the systemic circulation. The main metabolic pathways of SHEN211 were N-dealkylation, oxidative defluorination, glucuronidation, and glutathione conjugation. In addition, a physiologically based pharmacokinetic model for rats was constructed and validated using GastroPlus software, and the model was extrapolated to healthy adult males to predict the pharmacokinetic characteristics of SHEN211 in humans, providing invaluable insights into the human mass balance of SHEN211 and paving the way for clinical studies. SIGNIFICANCE STATEMENT: This study characterized the absorption, distribution, metabolism, and excretion of SHEN211, a 3CL^pro inhibitor for severe acute respiratory syndrome coronavirus 2 in rats. SHEN211 exhibited rapid absorption and was mainly distributed in the liver. Fecal excretion was the primary elimination route. The prediction of human pharmacokinetic characteristics using the physiologically based pharmacokinetic model provides an invaluable reference for optimizing the clinical dosing strategy of SHEN211 and advancing its ongoing clinical trials in China.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103623"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540640","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":"Corrigendum to \"Lansoprazole, a Proton Pump Inhibitor, Mediates Anti-Inflammatory Effect in Gastric Mucosal Cells through the Induction of Heme Oxygenase-1 via Activation of NF-E2-Related Factor 2 and Oxidation of Kelch-Like ECH-Associating Protein 1\" [The Journal of Pharmacology and Experimental Therapeutics 331 (2009) 255-264].","authors":"Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui, Toshikazu Yoshikawa","doi":"10.1016/j.jpet.2025.103631","DOIUrl":"10.1016/j.jpet.2025.103631","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103631"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484870","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":"Corrigendum to \"Artificial Oxygen Carriers-Past, Present, and Future-a Review of the Most Innovative and Clinically Relevant Concepts\": [The Journal of Pharmacology and Experimental Therapeutics 369 (2019) 300-310].","authors":"Katja B Ferenz, Andrea U Steinbicker","doi":"10.1016/j.jpet.2025.103632","DOIUrl":"10.1016/j.jpet.2025.103632","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103632"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484869","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":"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":"Exploring the therapeutic potential of aloenin-loaded nanogel for imiquimod-induced psoriasis-like skin conditions: In vitro and in vivo assessment.","authors":"Sadaf Jamal Gilani, Ehssan Moglad, Muhammad Afzal, Misbahuddin Rafeeq, Alaa Hamed Habib, Sami I Alzarea, Nadeem Sayyed, Imran Kazmi","doi":"10.1016/j.jpet.2025.103647","DOIUrl":"10.1016/j.jpet.2025.103647","url":null,"abstract":"<p><p>The purpose of this work was to evaluate the utilization of an aloenin-containing nanogel formulation as a carrier for the treatment of skin inflammation comparable to psoriasis. Imiquimod (IMQ) was used on mice to generate inflammation mimicking psoriasis. The probe sonicator-induced homogenization method was used to formulate nanogel particles with varying aloenin concentrations, namely 0.25% (NG1) and 0.5% (NG2). The nanogel was then assessed for appearance, size, zeta potential, spreadability, pH, in vitro diffusion, surface morphology (using scanning electron microscopy), and stability. Four groups were randomly selected among the animals: group I: normal control, group II: 1.5 mL IMQ control, group III: IMQ + 0.25% aloenin (NG1), and group IV: IMQ + 0.5% aloenin (NG2). Body weight, erythema, skin thickness scale, proinflammatory cytokine levels, oxidative stress, and histopathological examination were performed. According to the criteria used for the in vitro assessment, the nanogel formulation created had the necessary qualities. The particles had an average size of 79.1 nm, a polydispersity index of 0.200, and a surface charge of -27.7 mV. According to scanning electron microscopy examination, the nanogel was found to be spherical. The nanogel formulation effectively regulated in vivo parameters, including body weight, psoriasis area severity index, proinflammatory cytokines, and oxidative stress. According to the histopathological data, aloenin successfully healed damaged skin in IMQ-induced psoriasis-like inflammatory damage. Using this formulation, psoriatic symptoms could be effectively alleviated through the topical application of aloenin nanogel. As a potential treatment for psoriasis, the aloenin-nanogel formulation may be a beneficial and emerging trend in administering natural compounds in a more pleasant form. SIGNIFICANCE STATEMENT: This study reports the successful development of an aloenin-loaded nanogel that effectively treats imiquimod-induced psoriasis-like skin inflammation in vivo. The nanogel exhibited favorable physicochemical properties and significantly reduced inflammation, oxidative stress, and disease severity. Histopathological analysis confirmed improved skin healing. These findings demonstrate the therapeutic potential of natural compound-based nanogels as a safer and effective strategy for managing inflammatory skin disorders.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103647"},"PeriodicalIF":3.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883076","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":"Brain exposure of the mesenchymal-epithelial transition inhibitor savolitinib in nonhuman primates: A positron emission tomography study.","authors":"Peter Johnström, Zsolt Cselényi, Kowser Miah, Aurelija Jucaite, Graeme Scarfe, Miguel A Cortés González, Lars Farde, Christer Halldin, Karthick Vishwanathan, Magnus Schou","doi":"10.1016/j.jpet.2025.103638","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103638","url":null,"abstract":"<p><p>The receptor tyrosine kinase mesenchymal-epithelial transition factor inhibitor savolitinib is currently being evaluated as a treatment in non-small cell lung cancer (NSCLC) in combination with osimertinib. NSCLC patients with epidermal growth factor receptor/anaplastic lymphoma kinase mutations appear to have a high incidence (50%-60%) of brain metastasis; hence, cancer drugs that can efficiently access the brain hold a critical advantage. In this study, savolitinib blood-brain barrier penetration properties were investigated in nonhuman primates using positron emission tomography and intravenous administration of microdoses of [¹¹C]savolitinib either as a bolus or a bolus-constant infusion. Following a bolus, rapid distribution of radioactivity to the brain was observed reaching a maximum radioactivity concentration (C_max) of 0.33% of injected radioactivity. An estimated value of the concentration ratio of the total brain-to-plasma ratio (K_p) of 0.35 was derived using kinetic positron emission tomography data analysis. Intriguingly, notwithstanding the low C_max, the estimated unbound brain-to-plasma ratio using predetermined in vitro values for free fractions in brain and plasma showed a favorable brain-to-plasma partition with a K_p,uu of 0.65. This apparent contrast could be explained by the high free fraction of savolitinib in brain tissue. To further build confidence in the estimated K_p,uu, a bolus-constant infusion protocol successfully established a brain-to-plasma concentration steady-state yielding values for K_p and K_p,uu of 0.32 and 0.60, respectively, in good agreement with the bolus study. Our findings confirm blood-brain barrier penetrance and exposure of savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in NSCLC patients. SIGNIFICANCE STATEMENT: Patients with brain malignancies are challenging to treat due to the blood-brain barrier limiting the exposure of therapeutics to the central nervous system. This study demonstrates blood-brain barrier penetrance and exposure of the mesenchymal-epithelial transition inhibitor savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in non-small cell lung cancer patients.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103638"},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958359","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":"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}